TW200303748A - Method of treating osteoarthritis - Google Patents

Abstract

This invention relates to a method of preventing and treating osteoarthritis and inhibiting cartilage damage by administering a compound which is a 2, 3, 3a, 4, 5, 6, 7, 7a- octahydroindol-2-carboxylic acid, or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising the compound or salt thereof.

Description

200303748 发明 Description of the invention (The description of the invention should state: the technical field to which the invention belongs, the prior art, the content, the embodiments, and the drawings) [Technical Field of the Invention] The invention relates to a method for preventing and treating osteoarthritis ("〇A") and a method for inhibiting 5 cartilage damage by administering a compound of 2,3,3a, 4,5,6,7,7a-octahydroindole-2-carboxylic acid or a medicine thereof Acceptable salts, and a pharmaceutical composition comprising the compound or a salt thereof. BACKGROUND OF THE INVENTION 10 Many people who participate in physical activity suffer from sprains and torn cartilage due to physical activity. Furthermore, more than 23 million Americans have some form of arthritis. Of these different forms of arthritis, osteoarthritis ("OA") is the most prevalent and affects 20 million Americans. Osteoarthritis is mainly a condition of cartilage and bones under the cartilage, and contains other tissues in and around the affected joint. The result of a complex system that is related to mechanical, biochemical, and molecular mechanisms. Regardless of the source, patients suffering from cartilage damage experience pain, joint stiffness, joint stiffness, and subsequent inflammation that cause deformation, shrinkage, or loss of joint function. 〇 Ancient aspirin and the conventional non-steroidal anti-inflammatory drugs (NSAIDs) (coast isobutyrylpropionate, diclofenac, and methacrylic acid) can be used as / σ The main agent for the treatment of pain caused by cartilage damage, including pain related to pupae. These agents can inhibit the release of prostaglandins by blocking the conversion of arachidonic acid from the membrane of arachidonic acid through the regulation of oxidase 200303748 发明, description of the invention. However, treatment with conventional NSAIDs is limited by drug-related side effects, including life-threatening ulcers and kidney toxicity. Furthermore, each of these drugs can only treat secondary symptoms (such as pain) 'associated with cartilage damage or osteoarthritis. It is impossible to prevent or treat primary symptoms that have damaged cartilage 5. However, patients experiencing severe cartilage injury often do not require surgery often, including joint replacement surgery. Because traditional medicines used to prevent or treat disorders and diseases containing components of cartilage damage such as osteoarthritis have major disadvantages, there is a continuing need for new therapies for these diseases. We have now found that 10 2,3,3 &, 4,5,6,7,7 & _octahydroindole-2-carboxylic acid compounds or their pharmaceutically acceptable salts can be usefully used to prevent and inhibit cartilage Injury, relieve pain and prevent and treat osteoarthritis. Preventing and / or inhibiting all needs for cartilage damage, alleviating pain, and preventing and / or treating osteoarthritis, etc., can be administered to the patient in need of treatment according to the present invention-effective amounts of 2,3,3a, 4,5, 6,7,7a " '15indole-2-carboxylic acid or a pharmaceutically acceptable salt thereof. The content of the invention; | Summary of the invention The present invention provides: 1. A method for inhibiting soft f damage in mammals, which comprises administering 20 to a mammal-inhibiting effective amount of cartilage damage 2,3, 4,5, 6,7, ~ octahydroindole-2-carboxylic acid or a pharmaceutically acceptable salt thereof. Other specific embodiments of the method of the invention include: " 2. A method according to a specific implementation, wherein the 2,3,9,9,4,5,6,7 > The salt may be a mixture of all eight possible 200303748 hydrazones, stereoisomers as described in the invention, or pharmaceutically acceptable salts thereof. " 3. According to the specific implementation of the method, the 2,3,3a, 4,5,6,7,7a_ 5 10 15 two sides of the eight louse or its pharmaceutically acceptable salt can be eight possible stereo A mixture of any two of the isomers or pharmaceutically acceptable salts thereof. ㈣Specific embodiments! Method, wherein the 2,3,3M, 5,6,7,7a_ II: Gai ㈣ · ㈣ or a pharmaceutically acceptable salt thereof may be a possible stereoisomer or a pharmaceutically acceptable salt thereof A mixture of any three. / · The method according to the specific embodiment 1, wherein the 2,3,3M, 5,6,7,7a_ octadecanoic acid or a pharmaceutically acceptable salt thereof may be eight possible stereoisomers or a medicine thereof A mixture of any of the four acceptable salts. 6. The method according to the specific implementation of ⑷, wherein the 2,3,3a, 4,5,6,7,7a_ octabital acid or a pharmaceutically acceptable salt thereof may be eight possible stereoisomers or A mixture of any five of the pharmaceutically acceptable salts. 7. The method according to the specific implementation of ⑷, wherein the 2,3,3a, 4,5,6,7,7a_ Ertai 2-㈣ or its pharmaceutically acceptable salt can be eight possible stereoisomers or A mixture of any six of its pharmaceutically acceptable salts. 8. The method according to specific embodiment 1, wherein the 2,3,3a, 4,5,6,7,7a_dichloro «-contanoic acid or a pharmaceutically acceptable salt thereof can be eight possible stereoisomers Or a pharmaceutically acceptable salt of any of the seven species of the salt of X. 9. According to a specific example method, the 2,3,3a, mw octadecanoic acid or a pharmaceutically acceptable salt thereof may be ⑽, 3a⑻, 7a⑻] _2,3,33,4 , 5,6,7, ^ 八 气 〇 引 声 _2_Chinic acid disk 20 1 2⑻, MW to 2,3,3M, 5,6,7 ^^^ 2 A mixture of pharmaceutically acceptable salts. 200303748 发明, Description of the invention 10 · The method according to the specific embodiment 1, wherein the 2,3,3a, 4,5,6,7,7a-octahydrohydrogenated sigma-2-carboxylic acid or its pharmaceutically acceptable The double salt can be [2 (R), 3a (S) Ja (S)]-2,3,3a, 455,6,757a-octahydroindole-2-carboxylic acid and [2 (8), 3 & (11), 7 & (11)]-2,3,3 &, 4,5,6,7,7 & -octahydroindole-2-carboxylic acid or a mixture of 5 pharmaceutically acceptable salts thereof. 11. The method according to the specific embodiment 1, wherein the 2,3,3a, 4,5,6,7,7a_ octahydro 11 indole-2-metanoic acid or a pharmaceutically acceptable salt thereof may be [2 (S), 3a (R), 7a (S)]-2,3,3a, 4,5,6,7,7a-octazine sigma bow 丨 Homo-2-acid and [2 (foot), 3 & amp (8), 7 & (11)]-2,3,3 &, 4,5,6,7,73-octahydroindole-2-carboxylic acid or a mixture of 10 pharmaceutically acceptable salts thereof. 12. The method according to the specific embodiment 1, wherein the 2,3,3a, 4,5,6,7,7a- octa-IL, succinic acid or its pharmaceutically acceptable salt may be [2 ( S), 3a (S), 7a (R)]-2,3,3a, 4,5,6,7,7a-octahydroindole-2-carboxylic acid and [2 (11), 3 < 11) , 73 (8)]-2,3,3 &, 4,5,6,7,7 & -octahydroindole-2-carboxylic acid or a mixture of 15 medically acceptable salts thereof. 13. The method according to specific embodiment 1, wherein the 2,3,3a, 4,5,6,757a_ octahydroindole-2-carboxylic acid or a pharmaceutically acceptable salt thereof can be named as [2 (S ) 53a (S), 7a (S)]-2,353a, 4,5,6,7,7a-octahydroindole-2-carboxylic acid compound or a pharmaceutically acceptable salt thereof. 20 14. The method according to the specific embodiment 1, wherein the 2,3,3a, 4,5,6,7,7a-octahydroindole-2-carboxylic acid or a pharmaceutically acceptable salt thereof may be a name [2 (11), 3 & (11), 7 & (11)]-2,3,3 &, 4,556,7,73-octahydroindole-2-carboxylic acid or a pharmaceutically acceptable compound thereof Of salt. 15. The method according to specific embodiment 1, wherein the 2,3,3a, 4,5,6,7,7a- 200303748 玖, description of the invention octahydroindino-2-carboxylic acid, or a pharmaceutically acceptable The salt may be a compound named [2 (11), 3 & (8), 7 & (8)]-2,3,3 &, 4,5,657,73-octahydroindole-2-carboxylic acid or Its pharmaceutically acceptable salt. 16. The method according to specific embodiment 1, wherein the 2,3,3a, 4,5,6,7,7a-5 octahydro, 2-carboxylic acid or a pharmaceutically acceptable salt thereof may be named [2 (8), 3 & (foot), 7 & (trans)] _ 2,353 &, 4,5,6,7,7 octahydroindole-2-carboxylic acid compound or a pharmaceutically acceptable compound thereof Accepted salt. 17. The method according to the specific embodiment 1, wherein the 2,3,3a, 4,5,6,7,7a_ octachloro's-2-carboxylic acid or a pharmaceutically acceptable salt thereof can be named 1 〇 [2⑻, 3a (R), 7a⑻] -2,3,3 &, 4,5,657 ^ octahydroindole-2-weilic acid compound or a pharmaceutically acceptable salt thereof. 18. The method according to a specific embodiment], wherein the 2,3,3a, 4,5,6,7,7a_ octaazine-2-carboxylic acid or a pharmaceutically acceptable salt thereof may be named Laoshanyu, 7 ·)]-2), 3 ^ 4,5,6,7 ^ hydroindole_2_weilic acid or a pharmaceutically acceptable salt thereof.方法 The method according to the specific embodiment 1, wherein the 2,3,3a, 4,5,6,7,7a_ octahydro-2-carboxylic acid or a pharmaceutically acceptable salt thereof may be named hydrogen. Inducible _2_ acid compound or a pharmaceutically acceptable salt thereof. 2〇. The method according to the specific embodiment 1, wherein the 2,3,3a, 4,5,6,7,7 ^ octachloro Θ ΙΙ-2-carboxylic acid or a pharmaceutically acceptable salt thereof may be a name It is [taken], (3 noisy) ^ (8)]-2,3,3 &, 4,5,6,7,7 octahydroindole | weilic acid compound or a pharmaceutically acceptable salt thereof. The present invention also provides: 10 200303748 发明, description of the invention 21 · A method for preventing cartilage damage in mammals, 1 including 至 to mammals-effective amount of cartilage damage prevention 2,3,3a, 4,5,6, w Ba'e-2 side or its pharmaceutically acceptable salt. 5 Other specific embodiments of the method of the present invention include: 22. The method according to specific embodiment 21, wherein the 3, 4,5,6,7,73_octahydro__2, acid or pharmaceutically acceptable Salts: are all eight possible stereoisomers or their pharmaceutically acceptable salts: mixtures. 10 15 23. The method according to the specific embodiment 21, wherein the ',' 14'5,6'7,73-octadecyl_2_complete acid or its pharmaceutically acceptable is the eight possible A mixture of stereoisomers or pharmaceutically acceptable salts thereof. 24. The method according to the specific embodiment 21, wherein the 2,3,4,5,6,7,73_octahydro „induction_2, acid or a pharmaceutically acceptable salt thereof: is eight possible Stereoisomers or a mixture of any two of their pharmaceutically acceptable salts. 25. The method according to embodiment 21, wherein the 2,3,4,5,6,7, ~ octahydro__2_ The carboxylic acid or its pharmaceutically acceptable 1 may be a mixture of any of the four possible stereoisomers or its pharmaceutically acceptable salts. 26. The method according to the specific embodiment 21, wherein the ^: human ^ Octahydrogenic acid or its pharmaceutically acceptable ^ may be a mixture of any of the five possible stereoisomers or their pharmaceutically acceptable salts. 20 200303748 玖, Description of the invention 27. According to specific implementation The method of Example 21, wherein the 2,3,3 &, 4,5,6,7,7 & -octahydroindole-2-carboxylic acid or a pharmaceutically acceptable salt thereof can be eight possible stereoisomeric A mixture of any six of the compounds or pharmaceutically acceptable salts thereof. 5 28. The method according to embodiment 21, wherein the 2,3,3 &, 4,5,6,7,78-octahydroindane Indole-2-carboxylic acid or medicinally The accepted salt may be a mixture of eight possible stereoisomers or any of its seven pharmaceutically acceptable salts. 29. The method according to embodiment 21, wherein the 10 2,3,3 &, 4, 5,6,7,7 & -indolin-2-carboxylic acid or a pharmaceutically acceptable salt thereof may be [2 (8), 3 & (8), 7 & (8)] _ 253,3 & 5455,6,757 & -octahydroindole-2-carboxylic acid and [2 (11), 3 & (11), 7 & (11)]-2,3,3 &, 4,5,6,7, 7 & -octahydroindole-2-carboxylic acid or a pharmaceutically acceptable salt mixture thereof. 30. The method according to the specific embodiment 21, wherein the 15 2,3,3 &, 4,5,6,7 , 7 & -octahydroindole-2-carboxylic acid or a pharmaceutically acceptable salt thereof may be [2 (Magic, 33 (8), 7 # 8)]-2,3,3 &, 4,556,7, 7 & -octahydroindole-2-carboxylic acid and [2 (8), 3 & (11), 7 & (11)]-2,3,3 &, 4,5,6,7,7 &- Octahydroindole-2-carboxylic acid or a pharmaceutically acceptable salt thereof. 31. The method according to the specific embodiment 21, wherein the 20 2,3,33,4,5,6,7,7 &- The octahydroindole-2-carboxylic acid or a pharmaceutically acceptable salt thereof may be [2 (S) 53a (R), 7a (S)]-25353a5455,6,757a-octahydroindole-2-carboxylic acid And [2 (11), 3 & (8), 7 & (1〇) -2,353 &, 455,6,7573-octahydroindole-2-carboxylic acid or a pharmaceutically acceptable salt thereof. 32. The method according to the specific embodiment 21, wherein the 12 200303748 玖, invention description 2,3,3 &, 4,5,6,7,7 & -octahydroindole-2-carboxylic acid or medicament The acceptable salt on the bar may be [2⑻, 3a ⑻, 7a ⑽-2,3,3M, 5,6,7,7 ^ ϋ ^ 2_Μ Qi⑻々⑻, 7a⑻] -2,3,3a, 4, 5,6,7,7a • octahydro-2, acid = mixture of pharmaceutically acceptable salts. 5 33. According to the method of the specific embodiment 21, the method is 40,000, wherein the 2,3,3 &, 4,5,6,7,7 & -octahydroindole-2-carboxylic acid or its pharmaceutically acceptable The accepted pass may be a compound named [2 (S), 3a (S), 7a (S)]-25353a, 4,55657,7a-octaqiindole-2-carboxylic acid or a pharmaceutically acceptable compound thereof. Of salt. 34. The formula according to specific embodiment 21, wherein the 10, 2, 3, 3 &, 4, 5, 6, 7, 7 octahydroindole-2 carboxylic acid or a pharmaceutically acceptable The salt can be a compound named [2 (R), 3a (R), 7a (R)]-2,3,3a, 4,5,6 7 7a Pharmaceutically acceptable salt. 35. According to the formula of the specific embodiment 21, this ^ / 'wherein the 2,3,3 &, 4,5,6,7,7 & -octahydroindole-2-carboxylic acid or a pharmaceutically acceptable The hoof 15 may be named Baqi. A compound or a pharmaceutically acceptable salt thereof. 36. According to the specific embodiment 21, the formula, and the privately-owned compound, wherein the 2,3,314,5,6,7, is octahydroindole_2_carboxylic acid or a pharmaceutically acceptable salt thereof may be a name It is a compound of [2, 2 indole ~ 2-carboxylic acid or a pharmaceutically acceptable salt thereof. 37. The method according to the specific embodiment 21, wherein the 2,3,3a, 4,5,6,7,7a-octahydrogen | It is [2⑻, 3a (R), 7a⑻] _2,3,3μ, 5,6,7,7 & -octazine, a compound called indole-2-carboxylic acid or a pharmaceutically acceptable salt thereof. 13 200303748 发明, invention description 38. The method according to the specific embodiment 21, wherein the 2,353a5455,6,7,7a-octahydroindino-2-carboxylic acid or a pharmaceutically acceptable salt thereof can be named as [ A compound of 2 (R), 3a (S), 7a (R)]-2,353a, 4,5,6,757a-octazine-2-carboxylic acid or a pharmaceutically acceptable salt thereof. 5 39. The method according to embodiment 21, wherein $ 2,3,3 & 54,5,6,7,7 & -octahydro-2-carboxylic acid or a pharmaceutically acceptable salt thereof may be a A compound designated as [2 (S), 3a (S), 7a (R)]-2,353a5455,6,7,7a-octaazepine-2-weilic acid or a pharmaceutically acceptable salt thereof. 40. The method according to the specific embodiment 21, wherein a 10 π, wherein the 10,2,3,3 ^ 4,5,6,7,7 octahydroindole-2_carboxylic acid or a pharmaceutically acceptable The salt may be a compound named octahydro-2-carboxylic acid or a pharmaceutically acceptable salt thereof. The present invention also provides: 41. A method for treating osteoarthritis in mammals, comprising administering 15 medicines to a mammal in a therapeutically effective amount of 2,3,3 &, 4,5,6,7,7 Deca-2-carboxylic acid or a pharmaceutically acceptable salt thereof. Other specific embodiments of the method of the present invention include: 42. The method according to the specific embodiment 41, wherein the 2,3,3a, 4,5,6,7,7a. Human hydrogen is ten dollars Accepted salt 20 may be all eight possible stereoisomers or a pharmaceutically acceptable salt: mixture thereof. ^ A Wq method, wherein the 2,3,4,5,6,7,7 octahydro. Fruit_2_carboxylic acid or its pharmaceutically acceptable_ can be eight possible stereoisomers Or any of its pharmaceutically acceptable salts: 14 200303748 (ii) A mixture of the two. 44. The method according to embodiment 41, wherein the 2,3,3M, 5,6,7,7a-octahydrogen 2 side or its pharmaceutically acceptable pass can be eight possible stereoisomers or A mixture of any two of its pharmaceutically acceptable salts. 45. The method according to the specific embodiment 41, wherein the 2,3'3a, 4'5,6,7'7a_ 八 气 # 2, the acid or its pharmaceutically acceptable are the eight possible three-dimensional A mixture of any of the four isomers or pharmaceutically acceptable salts thereof. ίο 15 20 46. The method according to the specific embodiment 41, wherein the 3,3 &, 4,5,6,7, ~ octahydro-quinic acid or a pharmaceutically acceptable one thereof can be eight kinds. A mixture of five kinds of solid objects or their acceptable salts ^. 47. The method according to specific embodiment 41, wherein the 2,3,4,5,6,7,7 & _octahydroindole_2_carboxylic acid or a pharmaceutically acceptable one thereof: may be eight kinds of Any of the stereoisomers or their pharmaceutically acceptable salts: a mixture of six species. 48. The method according to the specific embodiment 41, wherein the 2'3,3 &, 4,5,6,7 > octadecyl. 2__ or its pharmaceutically acceptable sleep can be eight possible stereo Any of seven isomers or pharmaceutically acceptable salts thereof. 49. According to a specific embodiment 410,000 method, wherein the 2,3,3 ^ 4,5,6,7,7 octahydroindino-2-carboxylic acid or a pharmaceutically acceptable hydrazone may be [2 ( S), 3a⑻, 73⑻] _2,3 nine 4,5,6,7 | eight "^ 15 200303748 玖, invention description and [2 (11), 3 & (11), 7 & (1 ^ -2, 3,3 & 54,5,6,7,7 & -octahydroindole-2-carboxylic acid or a mixture of pharmaceutically acceptable salts thereof. 50. The method according to embodiment 41, wherein the 2,3 , 3 &, 4,5,6,7,7 & -octahydroindole-2-carboxylic acid or a pharmaceutically acceptable salt thereof 5 may be [2 (1〇, 3 & (8), 7 & ( 8)]-253,3 & 54,5,6,7,7 & _octahydroindole-2-carboxylic acid and [2 (S), 3a (R), 7a (R)]-2,3, 3a, 4,5,6,7,7a-octahydroindole-2-carboxylic acid or a pharmaceutically acceptable salt thereof. 51. The method according to the specific embodiment 41, wherein the 2,3,3 &, 4,5,6,7,7 & -octahydroindole-2-carboxylic acid or a pharmaceutically acceptable salt thereof 10 may be [2 (S), 3a (R) 57a (S)]-25353a54 , 55657,7a-octahydroindole-2-carboxylic acid and [2 (R), 3a (S), 7a (R)]-2,3,3a, 4,5,6,7,7a Hydroindole-2_carboxylic acid or a mixture of pharmaceutically acceptable salts thereof. The method of Example 41, wherein the 2,3,3 &, 4,5,6,7,7 & -octahydroindole-2-carboxylic acid or a pharmaceutically acceptable salt thereof 15 may be [2 (8) , 3 & (8), 7 & (11)]-2,3,3 & 54,5,6,7,7 & -octahydroindole-2-carboxylic acid and [2 (11) 53 & (1 〇, 7 & (8)]-2,3,3 & 54,5,6,7,7 & -octahydroindole-2-carboxylic acid or a pharmaceutically acceptable salt thereof. 53. According to the specific The method of embodiment 41, wherein the 2,3,3 &, 4,5,6,7,7 & -octahydroindino-2-carboxylic acid or a pharmaceutically acceptable salt thereof 20 may be named [ 2 (8), 3 & (8), 7 & (8)]-25353 &, 4,556,7,7 & -octahydroindole-2-carboxylic acid compound or a pharmaceutically acceptable salt thereof 54 The method according to the specific embodiment 41, wherein the 2,3,3 &, 4,5,6,7,7 & -octahydroindole-2-carboxylic acid or a pharmaceutically acceptable salt thereof may be a name [2 (11), 3 & (1〇, 7 & (11)]-2,3,3 &, 4,5,657,7 & -octahydroindole 16 200303748 玖, description of invention 嵘 -2-carboxylic acid The compound or a pharmaceutically acceptable salt thereof. 55. The method according to embodiment 41, wherein the 2,3,3 &, 4,5,6,7,7 & -octahydroindole-2-carboxylic acid or a pharmaceutically acceptable salt thereof may be a Compound named as [2 (1〇, 3 & (8) 57 & (8)]-2,3,3 &, 4,5,6,757 & -octahydroindole 5 嵘 -2 · carboxylic acid or its medicine 56. The method according to the specific embodiment 41, wherein the 2,3,3 &, 4,5,6,7,7 & -octahydroindole-2-carboxylic acid or a pharmaceutically acceptable salt thereof The accepted salt can be named as [2 (8), 3 & (11) 57 & (11)]-2,3,3 &, 4,5,6,7,7 & -octahydroindole_ A compound of 2-carboxylic acid or a pharmaceutically acceptable salt thereof. 10 57. The method according to the specific embodiment 41, wherein the 2,3,3 &, 4,5,6,7,7 & -octahydroindole -2-carboxylic acid or a pharmaceutically acceptable salt thereof may be named as [2 (S) 53a (R) 57a (S)]-253,3a, 45556,7,7a-octahydroindole-2- A compound of a carboxylic acid or a pharmaceutically acceptable salt thereof. 58. The method according to the specific embodiment 41, wherein the 15 2,3,3 &, 4,5,6,7,7 & _octahydroindole-2 -The carboxylic acid or a pharmaceutically acceptable salt thereof may be named as [2 (R), 3a (S), 7a (R)]-2,3,3a, 4,5,6,7,7a A compound of octahydroindole-2-carboxylic acid or a pharmaceutically acceptable salt thereof 59. The method according to the specific embodiment 41, wherein the 2,3,3 &, 4,5,6,7,7 & -Octahydroindino-2-carboxylic acid or a pharmaceutically acceptable salt thereof 20 may be named [2 (S), 3a (S), 7a (R)]-2,3,3a, 4,5 , 6,7,7a · octahydroindino-2-carboxylic acid compound or a pharmaceutically acceptable salt thereof 60. The method according to the specific embodiment 41, wherein the 2,3,38,4,5,6 , 7,7 & -octahydroindole-2-carboxylic acid or a pharmaceutically acceptable salt thereof may be named as [2 (R) 53a (R), 7a (S)]-25353a54,556,757a-eight Hydrogenin 17 200303748 玖, Description of the Invention Compound of indole-2-carboxylic acid or pharmaceutically acceptable salt thereof. The present invention also provides: 61 · -A method for preventing osteoarthritis in mammals, which comprises administering to breastfeeding Animals-An effective amount for preventing osteoarthritis is 2,3,3a, 4,5,6,7,7a-5 octahydroindolecarboxylic acid or a pharmaceutically acceptable salt thereof. Other specific embodiments of the method of the present invention Including: 62. The method according to the specific embodiment 61, wherein the 2,3,3M, 5,6,7,7a-octahydrobitalic acid or a pharmaceutically acceptable salt thereof may be 10 may be acceptable mixture of stereoisomers or a pharmaceutically acceptable salt of the eight kinds of portions. 63. The method according to the specific embodiment 61, which makes the 2,3,4,5,6,7, ~ octahydro octopazine or its pharmaceutically acceptable eight more possible A mixture of stereoisomers or any of its pharmaceutically acceptable salts. 15 64. The method according to the specific embodiment 6, wherein the '' 5,6,7,7a-Octoporex acid or its pharmaceutically acceptable is more than eight possible stereoisomers or its medicine Acceptable salt:

A mixture of the two. 1 J 20 65. The method according to embodiment 6, wherein the ^ M, 5,6,7,7a "L $ _2, acid or its pharmaceutically acceptable 7 is eight possible stereoisomers-four + Any of the following salts: · The method according to the specific embodiment 61, in which, a, 4,5,6,7,7a-octahydrofluorene _ μ eight " Accepted salts 18 200303748 (ii) The description of the invention may be a mixture of any of the eight possible stereoisomers or any of its pharmaceutically acceptable salts. 67. The method according to the specific embodiment 61, wherein the 2,3,3a, 4,5,6,7,7a-octahydro-2, acid or a pharmaceutically acceptable salt thereof can be eight possible stereo Any of the isomers or their pharmaceutically acceptable salts = a mixture of six. 68. The method according to the specific embodiment 61, wherein the 2,3,3 &, 4,5,6,7,7 octahydroindane "-2 'acid or" pharmaceutically acceptable more. 15 20 may be any of the eight possible stereoisomers or their pharmaceutically acceptable salts = a mixture of seven. 69. The method according to specific embodiment 61, wherein the 2,3,3a, 4,5,6,7,7a-octanoic acid 2 or its pharmaceutically acceptable can be [2⑻, 3a⑻, 7a⑻ ] -2,3,3M, 5,6,7,7a. Eight air ㈣ _ _ = = (2 (R), 3a (R), 7a (R))-2,3,3a, 4,5, 6,7,7a_ human hydrogen 〇 引 voc_2_ a mixture of tartaric acid or a pharmaceutically acceptable salt thereof. 7 0 · According to the specific implementation of Example 61, the ancient and also method 'wherein the 2,3,3M, 5,6,7,7a-octahydro-2-_ or its pharmaceutically acceptable: can be just , 3a⑻na)] _ 2,3,3M, ⑹, 7a_octa㈠M and [2⑻M), 73⑻] _2,3,3M, 5,6, π.M · ϋ_ A pharmaceutically acceptable salt mixture thereof. 71 · According to the specific implementation example 6〗 Xi + < method, wherein the 2,3,3a, 4,5,6,7,7a • human hydrogen ah 2 or «or a pharmaceutically acceptable salt thereof

Can be [2⑻, MR), 73⑻] · 2,3,3M, 5,6,7, ¥ Α Phenylacetic acid m2 (R), 3a (S), W 19 200303748 发明, the invention shows that it can be used in medicine Accepted salt mixture. 72. The method according to specific embodiment 61, wherein 2,3,3 &amp;, 4,5,6,7,7 &amp; -octahydroindino-2-carboxylic acid or a pharmaceutically acceptable pass thereof may be [ 2 (8), 348), 7411))-2,3,314,5,6 / 7,71 octahydroindole_2_guinic acid and [2 (R), 3a (R), 7a (S)]- A mixture of 2,3,3a, 4,5,6,7,7a-octahydroindole_2 • metanoic acid or a pharmaceutically acceptable salt thereof. 73. The method according to the specific embodiment 61, wherein Guhai 2,3,3 &amp;, 4,5,6,7,7 &amp; -octahydroindole-2-carboxylic acid or a pharmaceutically acceptable salt thereof may be A compound named [2 (S), 3a (S), 7a (S)]-2,3,3a, 455,6,757a-Yaoqikou 15 15 indole-2-carboxylic acid or its pharmaceutically acceptable Accepted salt. 74_ The method according to specific embodiment 61, wherein the 2,3,3a, 4,5,6,7,7a ^ Yindolin-2-carboxylic acid or a pharmaceutically acceptable salt thereof can be named as [2 (R), 3a (R), 7a (R)]-2,3,3M, 5,6,7,7a-A compound of octazol-2-carboxylic acid or pharmaceutically acceptable salt thereof . 75. The method according to the specific embodiment 61, wherein 2,3,3 &amp;, 4,5,6,7,7 &amp; -octahydroindole-2-carboxylic acid or a pharmaceutically acceptable one thereof is more preferably one. A compound named [2 (R), 3a (S), 7a (S)]-2,3,3a, 4,5,6,7,7a-octadecane or 11 -2-weilic acid or its compound Pharmaceutically acceptable salt. 76. The method according to the specific embodiment 61, wherein the 2,3,3 a, 4,5,6,7,7a-eight rat sigma-2 -weilaic acid or a pharmaceutically acceptable trip thereof may be a A compound named [2 (S), 3a (R), 7a (R)]-25353a, 4,5,6,7 7a · octazine indole-2-carboxylic acid or a pharmaceutically acceptable salt thereof . 77. The method according to specific embodiment 61, wherein 2,3,3 &amp;, 4,5,6,7,7 &amp; -eight rats are called Budu-2-weiric acid or a pharmaceutically acceptable trip thereof 20 200303748发明 The description of the invention may be a compound named [2 (8), 3 noisy), 7 &amp; ⑻] _2,3,3M, 5,6,7 7 &amp; _octahydroindole-2-carboxylic acid or a compound thereof Pharmaceutically acceptable salt. 78. According to a specific embodiment 61, the hydrazone / £ r, wherein the 2,3,3a, 4,5,6,7,7a · octahydrofluorene_2. The dicarboxylic acid or its pharmaceutically acceptable salt 5 may be − Designated as [2 (R), 3a⑻, 7a (R)] _ 2,3,3M, 5,6,7 7a_ octagas; a compound of indole-2-carboxylic acid or a pharmaceutically acceptable salt thereof. 79. The method according to the specific embodiment 61, wherein the 2,3,3 &amp;, 4,5,6,7,7 &amp; -octahydroindole-2-carboxylic acid or a pharmaceutically acceptable one thereof may be A compound named [2⑻, 3a⑻, 10 indole-2-carboxylic acid or a pharmaceutically acceptable salt thereof. 80. According to the specific embodiment 61, Fang Naifang, wherein the 2'3,3 &amp;, 4,5,6,7,7 &amp; -octahydroindole-2-carboxylic acid or a pharmaceutically acceptable _ may A compound named WRWaWJa⑻] _2,3,3 £ 1,4,5,6,7,7 &amp; -octahydro-0-nosing-2-carboxylic acid compound or a pharmaceutically acceptable salt thereof. 15 The present invention also provides: 81.-A method for alleviating pain in mammals, comprising administering to a mammal-a therapeutic amount of 2,3,3a, 4,5,6,7,7a 2_ Metabolic acid or a pharmaceutically acceptable salt thereof. Other specific embodiments of the method of the present invention include: 20 82. The formula according to specific embodiment 81 / '中 中 的 253,3 &amp;, 4,5,6,7,7 ^ octahydroindole-2-carboxylic acid Or a pharmaceutically acceptable salt thereof may be a mixture of all eight possible stereoisomers or a pharmaceutically acceptable salt thereof. 83. According to the method of specific embodiment 81, ▲ in the 21 200303748 玖, invention description 2,3,3 &amp;, 4,5,6,7,7 &amp; -octahydroindole-2-carboxylic acid or its pharmacological An acceptable salt may be a mixture of any of the eight possible stereoisomers or pharmaceutically acceptable salts thereof. 84. The method according to specific embodiment 81, wherein the 5, 2,3,3 &amp;, 4,5,6,7,7 &amp; -octahydroindole-2-carboxylic acid or a pharmaceutically acceptable salt thereof may be A mixture of any of the three possible stereoisomers or any of their pharmaceutically acceptable salts. 85. The method according to specific embodiment 81, wherein the 2,3,3 &amp;, 4,5,6,7,7 &amp; -octahydroindole-2-carboxylic acid or a pharmaceutically acceptable salt thereof 10 may be A mixture of any of the four possible stereoisomers or any of their pharmaceutically acceptable salts. 86. The method according to specific embodiment 81, wherein the 2,3,3 &amp;, 4,5,6,7,7 &amp; -octahydroindole-2-carboxylic acid or a pharmaceutically acceptable salt thereof may be eight A mixture of any of 15 possible stereoisomers or any of their pharmaceutically acceptable salts. 87. The method according to specific embodiment 81, wherein the 2,3,3 &amp;, 4,5,6,7,7 &amp; -octahydroindole-2-carboxylic acid or a pharmaceutically acceptable salt thereof may be eight A mixture of any of the six possible stereoisomers or pharmaceutically acceptable salts thereof. 20 88. The method according to the specific embodiment 81, wherein the 2,353 &amp;, 4,5,6,7,7 &amp; -octahydroindole-2-carboxylic acid or a pharmaceutically acceptable salt thereof can be eight possible A stereoisomer or a mixture of any seven of its pharmaceutically acceptable salts. 89. The method according to the specific embodiment 81, wherein the 22 200303748 玖, invention description 2,353a54,5,6,757a-octahydroindole-2-carboxylic acid or a pharmaceutically acceptable pass thereof may be [2 (8) , 3 &amp; (3), 7 &amp; (8)]-2,3,3 &amp;, 4,5,65757 Heart octahydro 13 lead 1 chestnut_2 _ # @ A mixture of pharmaceutically acceptable salts thereof. 5 90. The method according to the specific embodiment 81, wherein the 2,3,3 &amp;, 4,5,6,7,7 dioctahydro-2-feranoic acid or a pharmaceutically acceptable salt thereof may be [2 (R), 3a (S), 7a (S)] _ 2,3,3a54,5,65757a-octahydroline 7a (R)]-2,3,3a, 4,5,6,7,7a-O-Hydroxyπbow & its mixture of pharmaceutically acceptable salts. 10 91. The method according to the specific embodiment 81, wherein the 2,3,3 \ 4,5,6,7,7 & -octahydro, acyl-2-carboxylic acid or its pharmaceutically acceptable sleep Can be [2 (8), 3411), 7 & (8)]-2,3,33,4,5,6,7,71 Octahydro 11 lead _2_2 END 2 and [2 (R), 3a⑻, a mixture of pharmaceutically acceptable salts thereof. 15 92. According to the specific embodiment 81, the ether, soil 4, and heart method, wherein the 2,3,3a, 4,5,6,7,7a-octahydroπ-acid-2-carboxylic acid or its pharmacologically Acceptable trips can be [2⑻, 3a⑻, and [2 (R), 3a (R), 7a (S)]-2,3,3a, 4,5,6,7,7a-octahydron A mixture of acids or pharmaceutically acceptable salts thereof. 20 93. According to the specific embodiment 81, the formula ^ &lt; Wanfa, wherein the 2,3,3a, 4,5,6,7,7a-octahydroindole-2-carboxylic acid or its pharmaceutical Acceptable trips can be named as [2 (8) 53 啦), 7 啦) &gt; 25353 ^ 4,5,6,7,7 ^ octahydro ^. A compound of dor-2-carboxylic acid or a pharmaceutically acceptable salt thereof. 94. According to a specific embodiment, $ 1 of the formula &lt; Nai, wherein the 23 200303748, the invention description 2,3,3 &amp;, 4,5,6,7,7 &amp; -octahydroindox-2-carboxyl An acid or a pharmaceutically acceptable salt thereof may be named [2 (R), 3a (R), 7a (R)]-2,353M, 5,6,7,7a-octahydrogen | 嵊 -2- A compound of a carboxylic acid or a pharmaceutically acceptable salt thereof. 95. According to the specific example 81 of the ancient and ancient ^ 'go' wherein the 5, 2,3,3 &amp;, 4,5,6,7,7 &amp; octahydroindole_2_ carboxylic acid or its pharmaceutically acceptable The accepted pass may be a compound named [2⑻, 3_7 & (δ)]-2,3,3M, 5,6 7 7 ^, ^ indole-2-carboxylic acid or a pharmaceutically acceptable salt thereof. 96. According to the ancient method of the specific embodiment 81 * 'wherein the 2,3,33,4,5,6,7,7 £ 1-octahydroindole-2_carboxylic acid or its pharmaceutically acceptable The accepted Yue 10 can be a compound named [2⑻, 3_, 7 _] _ 2,3,3 &amp;, 4,5,6,7,7 &_octadecane; or a pharmaceutically acceptable compound thereof Acceptable salt. 97. The method according to the specific embodiment 81, wherein the 2,3,3 &amp;, 4,5,6,7,7 octahydroindole-2-carboxylic acid or a pharmaceutically acceptable salt thereof may be a It is named [2 (S) 53a (R), 7a⑻> 253,3 ^ 4,5,6,7,7. A compound or a pharmaceutically acceptable salt thereof. 98_ According to the specific embodiment 81 of the formula, Nai, wherein the 2,3,3 &amp;, 4,5,6,7,73-octahydroindole-2-carboxylic acid or a pharmaceutically acceptable salt thereof may A compound named [2 (R), 3a⑻, 7 &amp; (11)] _ 2,3,33,4,5,6,7,73_octahydro ^ indole-2-carboxylic acid or a pharmaceutically acceptable compound thereof Accepted salt. 9 9 According to a specific embodiment § 1 <Nai Li, wherein the 2,3,3 &amp;, 4,5,6,7> octahydroindole-carboxylic acid or its pharmaceutically acceptable favor It may be a compound named [2H, 2-H-carboxylic acid or a pharmaceutically acceptable salt thereof. 100. According to the method of specific embodiment 81, 1 〆, TT24 200303748 玖, invention description pharmaceutically acceptable salt 5 56'7,7a · octahydropyrene 2'3'3 &amp; '4,5,6, 7,7 &amp; -octahydro, 0-dodecanoic acid or its medical name is [2 (R), 3a (R), 7a (S)]-2, 3, 3a, 4 mouth- Compounds of 2-carboxylic acids or pharmaceutically acceptable salts thereof Other specific embodiments of the invention include: 5

M1. According to any one of the specific embodiments 81 to 100, the pain is inflammatory pain. The method wherein wherein ^ 2. According to any one of the specific embodiments 8 ″ ″。 The pain is bone and joint pain. 〆 103. According to any one of the specific embodiments 81 to 100, the pain is caused by cartilage damage. The invention also provides: 2,3 &gt;, 455,6,757 dioctahydro. And a pharmaceutically acceptable carrier 104 · -a pharmaceutical composition comprising an indole-2-carboxylic acid or a pharmaceutically acceptable salt thereof, a diluent, a diluent or an excipient. 15 Specific examples of other compositions of the present invention include: 105. The pharmaceutical composition according to specific example 104, wherein the pharmaceutical composition is a solid dosage form suitable for oral administration. Said. A pharmaceutical composition according to a specific embodiment, wherein the solid dosage form is a lozenge form. 20 Stomach 107. According to the pharmaceutical composition of Example 105, the solid d 罝 form in # is a capsule form. 108. The pharmaceutical composition according to specific embodiment 104, wherein the pharmaceutical composition is a kind of liquid suitable for intravenous administration or liquid administration by injection or oral or oral administration. Accepted vehicles are in solid dosage form. 25 200303748 发明, description of the invention A pharmaceutical composition in solid dosage form, which comprises a compound of Gang, 3a, 7 to 2, 3, 3, 5, 6, 7 &gt; Acceptable salts, and-pharmaceutically acceptable carriers, diluents or excipients. 5M The pharmaceutical composition according to the specific embodiment 109, wherein the pharmaceutical composition of the formula &gt; is suitable for oral administration. 111. The pharmaceutical composition according to embodiment 11 (), wherein the solid dosage form is a lozenge form. 112. The pharmaceutical composition according to embodiment 110, wherein the solid dosage form is a capsule form. Once the pharmaceutical composition according to the specific embodiment 109, wherein the solid dosage form of the pharmaceutical composition is suitable for intravenous administration or liquid injection for oral administration The vehicle is mixed. ⑴ The pharmaceutical composition 15 according to any one of the specific embodiments 104 to 113, wherein the 2,3,3a, 4,5,6,7,7a-octahydrotendo_2 · chitoic acid or a medicament thereof Acceptable salts exist in unit dosage form. The pharmaceutical composition according to any one of the items 1 to 4 in 113 in the specific embodiment 1, which is 2,3,3, 5,6,7,7 &amp; -octahydrotendo_2_quinic acid is acceptable The salt is in the amount of 1 mg to just 0 mg of unit dosage II = two 20. According to the pharmaceutical composition of any one of the specific embodiments 1 () 4 to 113, wherein the 2,3,3 &amp;, 4,5 , 6,7 &gt; Human hydrogen _2 acid or a pharmaceutically acceptable salt thereof is present in a unit dosage form in an amount of 5 mg to 500 mg. U7. The pharmaceutical composition according to any one of the specific embodiments 104 to 113, wherein the 2,3,3 &amp;, 4,5,6,7,7 &amp; -octahydroindole_2_carboxylic acid or its medicine On 26 200303748, the invention states that acceptable salts exist in unit dosage form in an amount of 10 mg to 500 mg. 118. The pharmaceutical composition according to any one of specific embodiments 104 to 113, wherein the 2,3,3a, 4,5,6,7,7a-octahydroindole-2-carboxylic acid or a pharmaceutically acceptable compound thereof Accepted salts are in unit dosage form in an amount of 20 mg to 500 mg. 5 119. The pharmaceutical composition according to any one of specific examples 104 to 113, wherein the 2,3,3 &amp;, 4,5,6,7,7 &amp; -octahydroindino-2-carboxylic acid or its Pharmaceutically acceptable salts are present in unit dosage form in an amount of 25 mg to 250 mg. 120. The pharmaceutical composition according to any one of specific embodiments 104 to 113, wherein 2,3,3 &amp;, 4,5,6,7,7 &amp; -octahydroindolo-2-acid Or a pharmaceutically acceptable salt thereof is present in unit dosage form in an amount of 50 mg to 250 g. 121. The composition according to any one of Embodiments 104 to 113, wherein the 2,3,3a, 4,5,6,7,7a-octahydroindole-2-carboxylic acid or Its pharmaceutically acceptable salts are present in unit dosage form in an amount of 50 mg to 200 mg. 122. The pharmaceutical composition 15 according to any one of the specific embodiments 104 to 113, wherein the 2,3,3 &amp;, 4,5,6,7,73-octahydroindole-2-carboxylic acid or The pharmaceutically acceptable salts are present in unit dosage form in an amount of 50¾ to 100¾ grams. 123. The pharmaceutical composition according to any one of specific embodiments 104 to 113, wherein the 25353a54,5,6J, 7a-octahydroindole-2-carboxylic acid or a pharmaceutically acceptable salt thereof is 5 mg Unit dosage forms exist in amounts of up to 50 mg. 201. Other specific embodiments of the present invention are a compound selected from the following: [2 (8), 3 &amp; (8) 57 &amp; (8)]-2,3,33,4,5,6, 7,7 &amp; -octahydro. Gongbuduo 1 Wei acid; [2 (R), 3a (R), 7a (R)]-2,3,3a, 4,5,6,7,7a-octahydron Gongbu chestnut · 2 side acid ; [2 (R) '3a (S), 7a (S)]-2,3,3a, 4,5,6,7,7a-At ^ n_ ^; 27 200303748 发明, Description of the invention [2 (8) '3 Zhuang (11), 7 &amp; (11)]-2,3,3 &amp;' 4,5,6,7,7 &amp; -octahydro. Gongbuduo_2_Wei acid; [2 (8), 3 巳 (11), 7 &amp; (8)]-2,3,3 Zhuang, 4,5,6,7,7 &amp; -octazine 11 0 果 _2- 酸酸; [2 (&amp;), 3 &amp; (8), 7 玨 (以)]-2,3,3 &amp;, 4,5,6,7,7 _2-Wei acid; [2 (8), 3 &amp; (8), 7 狂 (11)]-2,3,3 &amp;, 4,5,6,7,7 &amp; -octahydro ^ bow | 11 flowers _2-carboxylic acid; 5 and [2 (R), 3a (R), 7a (S)]-2,3,3M, 5,65757a-octahydro, fluorene-2-carboxylic acid or pharmaceutically acceptable Of salt. Other specific embodiments of the present invention include: 125 · —a kind of 2,3,3a, 4,5,6,7,7a-octahydroindone-2-acids or a mixture of pharmaceutically acceptable salts thereof, It may be a mixture of any of the eight possible stereoisomers or their pharmaceutically acceptable salts. 126. A mixture of 2,3,3 ^ 4,5,6,7,7 &amp; -octahydroindole_2-carboxylic acids or pharmaceutically acceptable salts thereof, which can be eight possible stereoisomeric species A mixture of any three of the compounds or pharmaceutically acceptable salts thereof. 127 · 2,3,3 &amp;, 4,5,6,7,7 & -octahydroindole_2_carboxylic acids or a mixture of 15 pharmaceutically acceptable salts thereof, which can be eight kinds A stereoisomer or a mixture of any four of its pharmaceutically acceptable salts. For example, 128 kinds of 2,3,3a, 4,5,6,7,7a-octahydroindole_2-carboxylic acids or a mixture of medically acceptable salts thereof, which can be eight possible stereo A mixture of any of the five isomers or pharmaceutically acceptable salts thereof. ２０129129 species of 2,3,3 &, 4,5,6,7,7 ^ octane mouth introductor 2-betal complex or a pharmaceutically acceptable salt mixture thereof, It may be a mixture of any of the eight possible stereoisomers or any of its pharmaceutically acceptable salts. A 130 · Species 253,3 &, 4,5,6,757 ^ octahydrodecapry-2-acid acid or a mixture of pharmaceutically acceptable salts thereof, which may be eight possible stereoisomers 28 200303748 玖, The invention description or a pharmaceutically acceptable mixture of any seven thereof. — · A mixture of 2,3,3 ^ 4,5,6,7,7 octahydroindolin-2-carboxylic acids or their pharmaceutically acceptable salts, which may be |; 2 (S) , 3a (S), 7a (S) &gt;, '4'5'6,7,7a- octahydroindolecarboxylic acid and [2⑻, ⑻] ·' &quot; 5'M'7a &quot; \ '2_ A mixture of a few acids or a pharmaceutically acceptable salt thereof. # 132 · A kind of 2,3,3M, 5,6,7,7 octahydrogen. A mixture of acid or its pharmaceutically acceptable salts, which can be [Liao, Qin], ¥)] · ,, '6'7,7a-octahydro is called | indole_2_carboxylic acid and [2⑻, 3 ^ r), ~ ⑻ ,, a, 4,5,6,7,7a &quot; L Duo acid or its medicine A mixture of acceptable salts. A mixture of 2,3,3a, 4,5,6,7,7a-octahydroindole-2_carboxylic acids or pharmaceutically acceptable salts thereof, which may be rigid, 3a (R) 7 Lu 2 , 3,3a, 4,5,6,7,7a-Human hydrogen. Gong Bu Duo 2_ m acid and [2⑻, 3a⑻, 7a (R)] _ 15 2,3, Qiu 4,5,6,7,7 &amp; _octahydro. Indole-2-carboxylic acid or a pharmaceutically acceptable salt thereof. 4 · 2,3,3 &, 4,5,6,7,7 &amp; -octahydromouth inducement _2. A mixture of a few acids or pharmaceutically acceptable salts thereof, which may be rigid and sweet 2,3,3M, 5,6,7,7a_Human Hydrogen Cutting_2_㈣ and Gang ^ ⑻ ^ ⑻] · 2〇2,3,33,4,5,6,7,7 "Hindol_2 _ Carboxylic acid or a pharmaceutically acceptable salt mixture thereof. Other specific embodiments of the present invention include: 135 ·-A method for treating mammalian cartilage damage, which comprises administering to the sprayed animal an effective amount for treating cartilage damage According to specific embodiment 124 29 200303748 玖, description of the invention ^, '3, 4,5,6,7,7 octahydroindole-2-bismuth 舻 · ^ pharmaceutically acceptable salts. A few or "wide. —A method for preventing cartilage damage in mammals, including “to 忒 feeding animals to prevent cartilage damage to any of m — Xiang Zhichuan“ according to specific examples ⑵ Yi Hua Hua M, Ba Qi Mei 2 · carboxylic acid Or its noble acceptable salt. A method for treating osteoarthritis of a mammal by heart, including administering a drug to the mammal-treating osteoarthritis spine, '° α Shuangli 23 3a4 S 6 7 7 10 according to any one of the specific embodiments 124 to 134, , M, 5,6,7,7 octahydroindole-2-carboxylic acid or a pharmaceutically acceptable salt thereof. 138. A method for preventing osteoarthritis in a mammal, comprising administering to the mammal-an effective amount for preventing osteoarthritis according to any one of specific embodiments m to 134 of 2,3,3 &amp;, 4,5 , 6,7, ~ Octahydrodecaline _2_guinea acid or a pharmaceutically acceptable salt thereof. 139. A method of alleviating pain in a mammal, comprising administering to the mammal an effective amount of alleviating pain according to any one of specific embodiments 124 to 134 of 2, 3, 3 & 4, 5, 6, 7 7 &amp; -octahydroindole-2-carboxylic acid or a pharmaceutically acceptable salt thereof. 140. A pharmaceutical composition comprising 2,3,3 &amp;, 4,556,7,7 &amp; -octahydroindole-2-carboxylic acid or a medicament thereof according to any one of specific embodiments 124 to 2034. A mixture of pharmaceutically acceptable salts, and a pharmaceutically acceptable carrier, diluent or excipient. 141. A pharmaceutical composition according to any one of specific embodiments 105 to 123, wherein the 2,353a5455, 6,757a ^ hydroindole-2-carboxylic acid or its medicine 30 200303748 Acceptable salts include 2,3,3 &amp;, 4,5,6,7,7 &amp; -octahydroindole_2-carboxylic acids according to any one of the specific examples 124 to 34 or a pharmaceutically acceptable Accepted salt mixture. Another specific embodiment of the present invention is: 142 ·-a combination of vadecoxib and a compound selected from: [2 (8), 3 &amp; (8), 7 &amp; (8)]-2 , 3,3 Zhuang, 4,5,6,7,7 &amp; -octahydroindole_2-carboxylic acid; [2⑻ &gt; (11), 7 &amp; (11)]-2,3,3 &amp;, 4, 5,6,7,7 &amp; -octahydroindole-2-chinic acid; [2 (11), 3 冱 (8), 7 &amp; (8)]-2,3,3 &amp;, 45556,7,7 &amp; -Octahydroindole_2-carboxylic acid; [2 (8) &gt; (11), 7 &amp; (11)]-2,3,33,4,5,6,7,7 &amp; -octahydro, [2 (8) '3 noisy), 7 la)]-2,3,3 &amp;, 4,5,6,7,7 &amp; -octahydroindole_2-metanoic acid; [2 (1 ^), 3 &amp; (8), 7 &amp; (&amp;)]-2,3,3 &amp;, 4,5,6,7,7 &amp; -octahydro, 17-2-2 acid; [2 (8), 3 &amp; (8), 7 Zhuang (11)]-2,3,3 &amp;, 4,5,6,7,7 &amp; -octahydro 1 »Gongbuduo_2_ Jun acid; And [2 (foot), 3 &amp; (11) 57 &amp; (8)]-2,3,3 &amp;, 4,5,6,7,7 &amp; -octahydroindole 17-b_2-carboxy15 acid or Pharmaceutically acceptable salt. Other specific embodiments of the present invention include: 143.-Vardecoxib and a 2,3,3 &amp;, 4,5,6,7,7 octahydroindole according to any one of specific embodiments 124 to 134 -2-carboxylic acid or a pharmaceutically acceptable salt thereof. ° Another embodiment of the present invention is: 144. A method for inhibiting cartilage damage in a mammal, comprising administering to the mammal a combination of a therapeutically effective amount of vardecoxib and a compound selected from the group consisting of: [ 2 (S), 3a⑻, 7a⑻] _2,3,33,4,5,6,7,7 &amp;. Octahydro.引 声 _2_traiter acid; 31 200303748 发明, description of the invention [2 (R), 3a (R), 7a (R)]-2,3,3M555657,7a ~ Ln_ ^; [2 (幻 ， 3 啦) ， 7 啦)]-2,3,9,4,55,657,7 bu ren called hydrogen || _2_2, slow acid; [2⑻, 3_, 7 _]-2,3,3M, 5,6,7,7μ "μ · 2 ^ [2⑻, [2 (11), 3La), 7 Noisy)] _ 2,3,3 ^ 55657,7 with a hydrogen mouth _2. Wei acid; [2 (8) 53La), 7_ ] -2,3,3 &amp;, 45556,7,7 &amp; -Human hydrogen, introduction of 0_2 Wei acid; and [2 (R), 3a⑻, 7a⑻] -2,3,3, 5,6 , 7,7 ^ 气 十 梁 _ Take acid or a pharmaceutically acceptable salt thereof. Another specific embodiment of the present invention is ... 10 145. A method for preventing cartilage damage in mammals, which includes the administration To a mammal, a therapeutically effective amount of vardecoxib and a combination selected from the group consisting of: [2⑻, [2 (R), 3a (R), 7a (R)] _ 2,3,3a, 4,5,6 , M + n_; 15 [2⑻, 3a⑻, 7a (S)]-2,3,3a, 4,5,6,7HDM_2__; [2 (8), 3_, 7 _]-2,3,3M, 5, 6,7,7 ^^^ _ 2__.

[2⑻, 3a (R), 7a ⑻] -2,3,3 £ 1,4,5,6,7,7 £ 1_octahydro + ^ slow acid. 5,6,7,7a.〇? 1 〇t.2.m ^; [2 (S) 53a (S), 7a (R)]. 2,3,3a, 455,657,7a.Ati〇? Int_2_m ^. 20 &amp; [2 (R), 3a (R), 7a (S)]-2,3,3M, 5,6,7,7a "Y | ^ mm acid or a pharmaceutically acceptable salt thereof. Another specific embodiment of the present invention is: 'its Including a combination of a method selected from the following 14 6 · —methods for treating osteoarthritis in mammals to a mammal in a therapeutically effective amount of vardecoxib and 32 200303748 玖, a combination of compounds described in the invention: [2 (8) , 3 &amp; (8), 7 &amp; (8)]-2,3,3 &, 4,5,6,7,7 & -octahydroindole 11 &gt; 1 &gt; 2-carboxylic acid; [2 (1 ^), 3 &amp; (11), 7 &amp; (&amp;)]-2,3,3 &amp;, 4,5,6,7,7 &amp; -octahydro 11 inductive 2-carboxylic acid; [2 (1 ^), 3 &amp; (8), 7 & (8)]-2,3,33,4,5,6,7,7 &amp; -octahydro 1 [2 (8) '3 &amp; (feet), 7 &amp; (feet)]-2,3,3 &, 4,5,6,7,7 & -octahydro 11 Noise &gt; &lt; &gt; 2- Wei acid; [2 (8), 3 &amp; (11), 7 &amp; (8) 1-2'3,3 &amp;, 4,5,6,7,7 &amp; -octahydro 11 bow Acid; [2 (feet), 3 & (8), 7 &amp; (feet)]-2,3,3du, 4,5,6,7,7 &amp; -Octahydroindone_2-complete acid; [2 (S), 3a (S), 7a (R)] _ 2,3,3a, 4,5,6,7,7a-octahydro, throat_2 · Wei acid; and [2 (R), 3a (R), 7a (S)]-2,3,3a, 4,556,7,7a-octahydroπ-gadobutorine 10 acid or its pharmaceutically acceptable Salt. Another specific embodiment of the present invention is: 147. A method for preventing osteoarthritis in a mammal, comprising administering to the mammal a combination of a therapeutically effective amount of vardecoxib and a compound selected from the group consisting of : 15 [2⑻, 3a (S), 7a⑻] _2,3,3a, 4,5,6,7,7a-octahydrogen, Hou_2 • rebel acid; [2 (Κ), 3α (Κ), 73 (Κ)]-2,3,3α, 4,556,757α-, νΑ〇? 1 ^ .2 ^^; [2 (R), 3a (S) '7a (S)]-2,3,3a, 4, 5,6,7,7a-octahydrotendo 1 carboxylic acid; f2 (S), 3a (R) '7a (R)]-2,3,3a, 4,5,6,7,7a- &gt; v ^ n2 __ ^; [2 (S), 3a (R) Ja (S)]-2,3,3a, 4,5,6,7,7a-octahydro is called pudor 1 carboxylic acid; 2〇 [2 (R) 3a (S) Ja (R)]. 25353a54? 5? 6JJa.A | L ^ | ^ .2 ^^.

[2 (S) '3a (S)' 7a (R)]-2,353a, 4,5,6,7,7a "4n? | N_ ^; and [2⑻, 3a⑻, 7a⑻ &gt; 2, 3, 3M, 5,657,7κ ^^ acid or a pharmaceutically acceptable salt thereof. Another specific embodiment of the present invention is: 33 200303748 chopping, invention description 148. A method for alleviating pain in mammals, comprising administering to the mouth milk Animal-A therapeutically effective amount of vardecoxib and a combination selected from the group consisting of: [2 (3), 3 &amp; (3), 7 & (8)]-2,3,3Μ55,657,7 ^^^^ 2 ^^; [2⑻, 3_ 雄)] _ 2,3,3 recognize 5,6,7,7 ^ hydrogen · 2 renegade acid; just, 3a⑻, 7a⑻] cut & 4,5,6,7 , ^ Hydrogen 2_new. [2⑻, 3_), 7 noisy)]-2,3,3 recognize 5,6,7,7 &amp; _octahydro + Do 2_slow acid. Ίο 15 20 [2 (R ), 3 ^), 7 ^ -2,3,3M, 55657,7a.A4L ^^ 2M ^; [2 (8), 3 ^ 8) ^-2,3,3M55 &gt; 6,7 &gt; 7 £ 1 .α | ι ^ Ιβ ^ 2 ^^; and baqi and citronilic acid, or a pharmaceutically acceptable salt thereof. Another specific embodiment of the present invention is: ⑷.-A poem composition comprising Valdecoxib and—A compound selected from the group consisting of: Gang, _), 7 willow_2, 3, nine, 4, 5, 6, 7, and 7 &amp;. ^^^ 2__. [2 (from calling 11), ¥ 明-2,3,3 ^ 5,6,7, ~ Octahydro coffee fruit _2_ 几 酸. [2 (^ 3 ^), 7 ^ 8) 1-2,3,3 ^ 4,5,6,7, [2⑻, 3_, 7_] · 2,3,3M, 5,6 , 7,7 ~ γ | ^^ 2__. Just, 3_, 7)) _ 2,3,3 from 5,6,7, ~ octahydro__2 ^ acid.

[, 3 啦), 7Ca-2,3,3 &amp;, 4,5,6,7,73_octahydro_ ^ acid. And [2 (R), 3a (R), 7a acetic acid or its pharmaceutical 'Acceptable salt' in combination with a pharmaceutically acceptable carrier 34 200303748 IX, description of the invention, diluent or excipient. Another specific embodiment of the present invention is: 150 · —a combination of etanercept-a compound selected from the following: [2 (S)? 3a (S) 57a (S)]-2,3? 3a? 455? 6J? 7a-/ \ 2- ^ Si; array), 3)), 7 &amp; ⑻ ^ ninety-seven from the mouth ^ octahydrotendo ^ Wei acid; [2 (R)? 3a (S) 57a ( S)]-2? 3? 3a545556? 7? 7a-y \ u ^ .2- ^ Si; [2 (8) 3α (Κ) ^ α (Κ)]. 25353M? 5? 6 ^^ α., νΑ ^, ^. 2 ^^; [2 (S), 3a (R), 7a (S) K, 3,3a, 4,556,7,7a ~ Y4 ^ t2_w; [2 (R)? 3a (S) 97a (R)]-25353a? 4? 5? 657? 7a-, v | L ^ | ^ .2 ^ gi; [2 (S), 3a (S), 7a⑻ &gt; 25353M, 5565757 ^ octahydro_2_ Acid; and [2 (R), 3a (R), 7a (S)]-2,3,3a54,556,757a-octahydroindole · 2_ acid, or a pharmaceutically acceptable salt thereof. Other specific embodiments of the present invention include: 151 · —an etanercept and a 2,3,3 &amp;, 4,5,6,7,7 &amp; -eight according to any one of the specific embodiments 124 to 134 A combination of hydroindole-2-carboxylic acid or a pharmaceutically acceptable salt thereof. Another specific embodiment of the present invention is a method of inhibiting cartilage damage in a mammal, which comprises administering to the mammal a combination of a therapeutically effective amount of etanercept and a compound selected from the following compounds: [2 (S), 3a (S), 7a (S)]-2,3,3a, 4,5,6,7,7a ~ 1n3n_ ^; [2 (Magic, 3La), 7 & ⑻]- 2,3,3 &, 4,5,657 &gt; Octahydro 5 team 2 acid only; [2 (R), 3a⑻, 7_ &gt; 253,3M, 5,6,7,7α &quot; γ4 ^ κ · 2_ ^; 35 200303748 发明, description of the invention [2 (8; »(11) '7 & (11)]-2,3,3 &amp;, 4,5,6,7,7 &amp; -octahydro 1? 引 1} 朵 _2 _Weic acid; [2 (8) &gt; (11) '7 &amp; (8)]-2,3,9,4,5'6,7,7 &amp; -octahydro 11 Gongbuduo_2_Weic acid; [ 2 (R), 3a (S) 57a (R)]-2,353a, 4,5,6,7,7a-octahydro is called | 〇 朵 _2_ Wei acid; [2 (8), 3 &amp; (8) , 7 汪 (11)]-2!) 3,3 &amp;, 4,5,6,7,7-octahydro 11 lead 11 flowers _2_wei acid · 5 and [2⑻, 3a⑻, 7 friends)]] -2,3,3 &amp;, 4,5,6,7,7 &amp; -octahydro "Introduction-2_Brancid acid or a pharmaceutically acceptable salt thereof. Another specific embodiment of the present invention is: 153 · A method for preventing cartilage damage in mammals, which comprises administering to a mammal a therapeutically effective amount Combination of etanercept and a compound selected from the following compounds: [2 (8), 38 (8), 7 &amp; (8)]-2,3,3, 4,5,6,7, 7 & -octahydro1! Gongbuduo_2-Wei acid; [2 (11), 3 &amp; (11), 7 &amp; (11)]-2,3,3 &amp;, 4,5,6,7, 7 &amp; -octahydroindole_2-carboxylic acid; [2 (R), 3a (S), 7a (S)]-2,3,3a, 4,5,6,7,7a-octahydroindole _2_antacid; [2 (S), 3a (R), 7a (R)]-2,3,3a, 4,5,6,7,7a-octahydroindole_2-carboxylic acid; 15 [2 (8), 3 &amp; (foot), 7 &lt; 8)]-2,3,3 ^ 4,5,6,7,7 &amp; -octahydroindole_2_carboxylic acid; [2 (trans) , 3 &amp; (8), 7 &amp; (Chinese)]-2,3,3 &amp;, 4,556,757 octahydroindole_2-carboxylic acid; [2 (8), 3 &amp; (8) 57zhuang (11)] -2,3,3 &amp;, 4,5,6,7,7 &amp; -octahydro-5buri.2-Amino acid; and [2 (R), 3a (R), 7a (S)]-2, 3,3a, 4,5,6,7,7a-octahydrochinokyl-2-ene acid or a pharmaceutically acceptable salt thereof. 20 Another specific embodiment of the present invention is: 154.-A method for treating osteoarthritis in a mammal, comprising administering to the mammal a therapeutically effective amount of etanercept and _ selected from the following compounds Combination: [2 (8), 3 Zhuang (8), 7 &amp; (8)]-2,3,3 &, 4,5,6,7,7 &amp; -octahydroin-2-weiric acid; 36 200303748 发明, description of the invention [2 (R), 3a (R), 7a (R)]-2,3,3a, 4,5,6,7,7a-octahydrou Gongbuli 酉 transformation · [2 (11) , 3 &amp; (8), 7 &amp; (8)]-2,3,3 &amp;, 4,5,6,7,7 &amp; -octahydro 11 bows 丨 13 racks &lt; _2_chinic acid. [2 (8 ), 3 冱 (11), 7 &amp; (11)]-2,3,3 &amp;, 4,5,6,7,7 &amp; -octane called Buzhuang-2_Wei Fufu [2 (S), 3a (R), 7a (S)] _ 2,3,3a, 4,5,6,7,7a_octahydroindone_2 ^ acid; 5 [2 (1〇, 3 &amp; (8) 57 狂 (11 )]-2,3,335455,6,7,7 octahydro-octahydro, vocabulary acid; [2 (8), 3 冱 (8), 7 &amp; (11)]-2,3,3 &amp; ， 4,5,6,7,7 &amp; -octahydro 11 Gongboduo_2 edge acid. And [2 (R), 3a (R), 7a (S)]-2,3,3a, 4,5 , 6,7,7a-octahydrosigma induces _2_ acid and its pharmaceutically acceptable salt. Another specific embodiment of the present invention is: 10 155 · A method for preventing osteoarthritis in mammals Comprising a combination of a therapeutically effective amount of etanercept and a compound selected from the group consisting of: [2 (S), 3a (S), 7a (S)]-2, 3, 3a administered to the mammal. ， 4,5,6,7,7a-octahydron bow | Acoustic acid; [2 (11), 3 Zhuang (11), 7 Mu (11)]-2,3,3 &amp;, 4,5, 6,7,7 & -octahydroindole_2-carboxylic acid; 15 [2 (foot) '3 啦), 7 啦)]-2,3,3 ^ 4,5,6,7,7 &amp;- Octahydroindole_2-brasic acid; [2 (8), 3 &amp; (11), 7 & (11)]-2,3,3 &amp;, 4,5,6,7,7 &amp; -octahydroindane Indole_2_carboxylic acid; [2 (S), 3a (R), 7a (S)]-2,3,3a, 4,5,6,7,7a · octahydroindole · 2 · metanoic acid [2 (11), 3 &lt; 8), 7 &amp; (11)]-2,3,3 &amp;, 45556,7,7 &amp; -octahydroindole-2_carboxylic acid; [2 (8) &gt; (8), 7 & (101-2, 3, 3 &amp;, 4,5,6,7,7 &amp; -octahydroindole-2_carboxylic acid; 20 and [2⑻, 3a (R), 7a⑻ ] -2,3,3M, 5,6,7 Ja-octahydroindium-2-carboxylic acid or a pharmaceutically acceptable salt thereof. Another specific embodiment of the present invention is: 156.-A method for alleviating pain in mammals, comprising administering to the mammal a therapeutically effective amount of etanercept and a compound selected from the following compound 37 200303748 The combination of explanation: [2 (8), 3 &amp; (8), 7 &amp; (8)]-2,3,3 &amp;, 4,5,6,7,7 &amp; -octahydro called 丨 voc_2_2 &gt;Acid; [2 (11), 3 &amp; (11), 7 & (11)]-2,3,3 &amp;, 4,5,6,7,7 &amp; -octahydroportal bow | vocal_2_ [2 (1 ^), 3 &amp; (8), 7 &amp; (8)]-2,3,3 &amp;, 4,5,6,7,7 &amp; -octahydrogen. Lead 11 flowers> _2_ ^ acid; 5 [2 (S), 3a (R), 7a (R)]-2,3,3a, 4,5,6,7,7a-octahydrosigma bow | Voice_ 2 -_ ^^ acid, [2 (8), 3 Wang (11), 7 &amp; (8)]-2,3,3 &amp;, 4,5,6,7,7 _2_traiter acid; [2 (1 ^), 3 &amp; (8), 7M (11)]-2,3,3 &amp;, 4,5,6,7,7 &amp; -octahydro. Introduce 11 _2-traiters; [2 (8), 3 &amp; (8), 7 carry (11)]-2,3,3 &amp;, 4,5,6,7,7 &amp; -octahydrocall | Vocal_2_1 酉 man; and [2 (R), 3a (R), 7a (S)]-2,3,3a, 4,5,6,7,7a-octahydro〇 bow | @ 敌 10 酸 ， Or a pharmaceutically acceptable salt thereof. Another specific embodiment of the present invention is: 157.-A pharmaceutical composition comprising etanercept and-a compound selected from the group consisting of: [2 (8), 3 (8), 7 &amp; (8) ] -2,3,3 &amp;, 4,5,6,7,7 &amp; -octahydroindole_2_metanoic acid; 15 [2 (to), 3 &amp; (Chinese), 7 &amp; (to)]- 2,3,3 &amp;, 4,5,6,7,7 &amp; -octahydropyrene_2_slow acid; [2 (Magic, 3 &amp; (8), 7 & (8)]-2,3, 3 &amp;, 4,5,6,7,7 &amp; -Octahydro is called indole_2_rebel acid; [2 (S), 3a (R), 7a (R)] _ 2,3,3a54,5,6 , 7,7 octahydroindole · 2 acid only; [2 (8), 3 &amp; (1〇, 7 & (8)]-2,3,3 &amp;, 4,5,6,7,7 &amp; -Octahydroline_2 edge acid; [2 (R), 3a (S), 7a (R)]-2,3,3a, 455,6,7,7a &quot; 2〇 [2⑻, 3 &amp; (8), 7 &amp; (11)]-2,353 ^ 4,556,7,7 &amp; -octahydro, indole | metanoic acid; and [2 (幻 533 化) &gt; (8)]- 2,3,3 &amp; 54,5,6,7,7 &amp; -octahydro 13 Gongbuduo_2_ renegade acid or its medicinal ability, and Xiao Yiyi medicable #susceptible carrier, A diluent or an excipient together. Another specific embodiment of the present invention is: 38 200303748 玖, description of the invention 158 · an inflixima b) in combination with a compound selected from: [2 (8), 3α (8), 7_ &gt; 2, 3, 3M, 5, 6, 7, 7M ^ K · 2 · ^; [2 (R) 53a (R) Ja (R)]. 2? 353a? 4? 5? 6J57a.A ^^, ^^ m ^. 5 [2⑻, 3a ⑻, 7 &amp; (8)]-2,3,3 &amp;, 4,5,657,7 &amp; -octahydro.Gongbuduo_2_weilic acid; [2 (S), 3a (R), 7a (R)]-2,3,3a, 4,5,6,7, 7a ~ \ | ^ t2 __ ^; [2 (8), 3 &amp; (11), 7 & (8)]-2,3,3 &amp;, 4,5,6,7,7 &amp; -octahydroindole | Wei acid; [2 (11) '3 &amp; (8), 7 &amp; (11)]-2,3,3 &, 4,5,6,7,7 &amp; -octahydroindole_2_complete acid; [2 (8) &gt; (8), 7 &amp; (11)]-2,3,3 &amp;, 4,5,657,7 & -octahydroindole. 2_weilic acid; 10 and [2⑻, 3a (R ), 7a (S)]-2,353a545556,7,7a-octahydrohydroxamic acid or a pharmaceutically acceptable salt thereof. Other specific embodiments of the present invention include: 159 · —Influx Mapper and a 2,3,3 &, 4,5,6,7,7 &amp; according to any one of the specific embodiments 124 to 134 -A combination of octahydroindino-2-carboxylic acid or a pharmaceutically acceptable salt thereof. Another specific embodiment of the present invention is: 160. A method for inhibiting cartilage damage in mammals, comprising administering to a mammal a combination of a therapeutically effective amount of Inflix Marble and a compound selected from the group consisting of: 20 [2⑻, 3a⑻, ~ (8) &gt; 25353α, 4,5,6,7,7α-octahydroindole 1 carboxylic acid; [2 (R), 3a (R), 7a (R)]-2 , 3,3a, 4,5,6,7,7a-octahydropyrene · 2-acid acid; [2 (R), 3a (S), 7a (S)]-2,353a, 4,5,6 , 7,7a-octahydroindolin-2-phosphonic acid; f2 (S), 3a (R), 7a (R)]-2,3,3a, 4,5,6,7,7a-octahydroindolin Indole-2-carboxylic acid; [2 (8), 3 &amp; (11), 73 (8)]-2,3,3 &amp; 54,556,7,7 &amp; -octahydroindane, 2-carboxylic acid; 39 200303748发明, description of the invention ⑻, 7a ⑻] _2,3,3a, 4,5,6,7,7a_ octahydrom slow acid; [2⑻, 3a⑻, 7a (R)]. 2,3,3a, 4,5 , 6,7,7a_A | ^ d ^; and [2 (R), 3a⑻, 7 rings] -2,3,3 &amp;, 4,5,6,7,7 £ 1_octahydro, throat_2_ Metabolic acid or a pharmaceutically acceptable salt thereof. 5 Another embodiment of the present invention is: 161. A method for preventing cartilage damage in a mammal, comprising administering to the mammal a therapeutically effective amount of Inflix Mapper and a compound selected from the following compounds: Combination: [2 (8), 3 &lt; 8), 7 &lt; 8)]-2,353 ^ 5,65757 cardiohydroindole_2-metanoic acid; 10 [2 (11), 3 &amp; (] ^), 7 &lt; Foot)]-2,3,3 &amp;, 4,5,657,7 &amp; -octahydroindole_2_carboxylic acid; [2 (1 ^) '3 &amp; (8), 7 &amp; (8)]-2 , 3,3 &amp;, 4,5,6,7,7 &amp; -octahydro. Gong Bu Duo_2_renic acid · [2 (8), 3 &amp; (foot), 7 &amp; (11)]-2,3,3 &amp;, 4,5,6,7,7 &amp; -octahydro. Gongbuzhuang_2-renegade acid [2 (8), 3 mad (11), 7 &amp; (8)]-2,3,33,4,556,7,7 &amp; -octahydro〇 bow | throat_2- [2 (called 3 &amp; (8), 7mad (11)]-2,3,33,4,5,6,7,7 &amp; -octane called | Hou_2 edge acid; 15 [2 (3), 3 &amp; (8), 7 &amp; (foot)]-2,3,3 &amp;, 4,556,7,7 &amp; -octahydroindole_2_rebel acid; and [2 (R), 3a ( R), 7a (S)]-2,3,3a, 4,5,6,7,7a-Octahydrosigma bowburi · 2-guineadioic acid or a pharmaceutically acceptable salt thereof. Another embodiment of the present invention The embodiment is: 162. A method for treating osteoarthritis in a mammal, which comprises administering to the mammal a therapeutically effective amount of Inflix Mapper and a combination selected from the following compounds: [ 2 (S) 53a (S), 7a (S)]-2,3,3a, 4,5,6,7,7a-octahydroindole_2 · metanoic acid; [2 (11) 53 &amp; (11) ), 73 (Chemical)]-253,3 &amp; 545556,7578-octahydroindole melanoic acid; [2 (Chemical), 3 &amp; (8), 7 &amp; (8)]-2,3,3 &amp;, 4,5,6,7,7 &amp; Octahydro-2 edge acid; 40 200303748 玖, Description of the invention [2 (S), 3a (R), 7a (R)]-2, 3, 3a, 4 ,, 5,6,7,7a-octahydroindole acid; [2 (8) 53 &amp; (foot) 57 & (8) 1-2,3,3 &, 4,5,6,7,7 ^ 8 Hydroindole_2_rebel acid; [2 (1 〇, 3 &amp; (8), 7 &amp; (11)]-2,3,3 &amp;, 4,5,6,7,7 Mad-octahydro 11 lead 11 _21_ rebel acid; [2 (S) ， 3a (S), 7a (R)]-2,3,3a, 4,5,6,7,7a-octahydroπ bow 丨 Hou · 2_ Wei acid · 5 and [2 (R), 3a ( R), 7a (S)]-253,3a, 4,556,757a-octahydrobone 丨 @ _2-betotic acid or a pharmaceutically acceptable salt thereof. Another specific embodiment of the present invention is: 163.-a kind of prevention of breastfeeding A method for osteoarthritis of an animal, comprising administering to a mammal a therapeutically effective amount of a combination of Inflix Mapper and a compound selected from the group consisting of [2 (8), 3 &amp; (8), 7 &amp;; (8)]-2,3,3 &amp;, 4,5,6,7,7 &amp; -octahydrobamboo_2-rebellion acid [2 (R), 3a (R), 7a (R) ] -2,3,3a, 4,5,6,7,7a &quot; Ln Chinic Acid; [2 (R)? 3a (S)? 7a (S)]-2? 353a5455? 6? 7? 7a-y \ ^; [2 (S), 3a (R) 57a (R)]-253,3a54,5565757a-Human hydrogen + Duo · 2-Jinic acid; [2 (S), 3a (R), 7a (S) ] -2,3,3a, 4,5,6,7,7a &quot; Ln ^; [2 (R)? 3a (S) Ja (R)]. 2? 3? 3M? 5? 6JJa.AA ^^ .2 ^^; Gang, and [2 (R), 3a (R) ja ⑻⑷ added from ^ qi Qi Shi Li ^ slow acid or a pharmaceutically acceptable salt thereof.

2U Another specific embodiment of the present invention is: 164. A method for alleviating pain in a mammal, comprising administering to the mammal-a therapeutically effective amount of Intex Marble and-a combination selected from the following compounds: -2-carboxylic acid [2 (S), 3a (S) Ja (S)]-253,3a, 4,55657,7a &quot; \ t ^^ 200303748 玖, description of the invention [2 (1 ^), 3 压 ( 11), 7 &amp; (11)]-2'3,3 &, 4! &Gt; 5,6,7,7Kang-octahydro 5 | Voice &gt; _2 &lt; &gt; &gt; Rebel acid [2 (11 ), 3 &amp; (8), 7 &amp; (8)]-2,3,3 &amp;, 4,556,7,7 &amp; -octahydro, indole-24 acid; [2 (8), 3 &amp; (magic, 7mad (11)]-2,3,3 &amp;, 4,5,6,7,7 &amp; -octane is called | 17 柒 _2_ ^ 酉 change.

[2 (8), 3 mad (11), 7 &amp; (8)]-2,3,3 &amp;, 4,5,6,7,7 &amp; -octahydro. Bow | 17 flowers &lt; 1 &gt; 2_ ^ 酉 复 · 5 [2 (1〇, 3 &amp; (8), 7 &amp; (11)] _ 2,353 &amp;, 4,5,6,7,7 &amp; -octahydro Indole_2-chinic acid; [2 (S), 3a (S), 7a (R)]-2,3,3a, 4,5,6,7,7a-octaqi sigma bow | And [2 (R), 3a (R), 7a (S)]-2,3,3a, 4,5,6,7,7a-octahydro is called bado-2_ ^ acid or its pharmaceutically acceptable Salt. Another specific embodiment of the present invention is: 10 165 · A pharmaceutical composition comprising Inflix Mapper and a compound selected from the group consisting of: [2 (S), 3a (S), 7a ( S)]-2,3,3a, 4,5,6,7,7a-octahydrosigma sigmadol; [2 (11), 3 carry (11), 7 &amp; (11)]-2, 3,3 &amp;, 4,5,6,7,7 &amp; -octahydroindole 0 &lt; &gt; &gt; 2_rebel acid; [2 (化) 53 &amp; (8), 73 (8)]-2 , 3,3 &amp;, 4,5,6,7,7 &amp; -octahydroindole-2-carboxylic acid; 15 [2 (8), 3 noisy), 7 noisy) &gt; 2,3 nine 4,5 , 6,7,7 &amp; -octahydroindole_2_ Junic acid; [2 (8), 3 noisy), 7 la)]-2,3,3 &amp;, 4555657,7 ^ octahydroindole_2 _Rebel acid; [2 (1〇, 3 &amp; (8), 7 &amp; (11)]-2,3,3 &amp; 54,5,6,7,7 &amp; -octahydroindole_2_rebel acid; [2 (S), 3a (S), 7a (R)]-2,3,3a, 4,5,6,7,7a &quot; ^ n_ ^; and [taken], 3 &amp; (11), 7 &amp; (8)]-253,3 & am p; 5455,657,7 &amp; -octahydroindole-2 side 20 acid or its pharmaceutically acceptable hydrazone, together with a pharmaceutically acceptable carrier, diluent or excipient. Another specific embodiment of the present invention is: 166 · —a combination of aminoamidofolate and a compound selected from the group consisting of: [2 (S), 3a (S), 7a (S)]-253, 3a, 4,556,7,7a-A | ^ | n_; 42 200303748 玖, description of the invention [2 (11), 3 &amp; (11), 7 pattern (11)]-2,3,3 Zhuang, 4,5,6, 7,7 random-octahydroindole-2-weiric acid; [2 (11), 33 (8), 73 (8) '-2,353 &amp;, 4,55657,7 &amp; -octahydroindole-2- Acid; [2 (8), 3 &amp; (11), 7 &amp; (11)]-2,3,3 &amp;, 4,5,6,7,7 [2 (8), 3 &amp; (11), 7 &amp; (8)]-2,353 &amp;, 4,5,657,7 &amp; -octahydroindole-2-weilic acid; 5 [2 (11), 348), 7 & (1〇 &gt; 2,3,3 &amp;, 4,5,6,757 &amp; -octahydroindole-2-carboxylic acid; [2 (S), 3a (S), 7a (R)]-2 , 3,3a, 4,5,6,7,7a-octahydro 0 Gongbuduo-2-brasic acid; and [2 (R), 3a (R), 7a (S)]-2,3,3a , 4,5,6,7,7a-octahydrosigma acid or a pharmaceutically acceptable salt thereof. Other specific embodiments of the present invention include: 1067. An aminomethylfolate and a 2,3,3 &amp;, 4,5,6,7,7 &amp; -octahydro, glutamic acid or a pharmaceutically acceptable salt thereof according to any one of Examples 124 to 134 Combination. Another specific embodiment of the present invention is: 168. A method for inhibiting cartilage damage in a mammal, comprising administering 15 to the mammal a therapeutically effective amount of aminomethylfolate and a compound selected from the group consisting of Combination: [2 (8), 3 &amp; (8), 7 & (8) &gt; 2,3,3 &amp; 54,556,757 &amp; -octahydroindole_2-carboxylic acid; [2 (11), 38 ( 11), 7 &amp; (11)]-2,3,33,4,5,6,7,7 &amp; -octahydrogen. Introduced -2-complete acid; [2 (1 ^), 3 &amp; (8 ), 7 &amp; (8)]-2,3,3 &amp;, 4,5,6,7,7 &amp; -octahydro 5 丨! 3 _2-weilic acid; 2〇 [2 (S), 3a ( R), 7a (R)]-2,3,3a5455,6,7,7a-octahydroindolecarboxylic acid; [2 (8), 3 &amp; (11), 7 &amp; (8)]-253,3 &amp;, 455,6,7,7 octahydroindole-2-carboxylic acid; [2 (11), 3 &amp; (8), 7 &amp; (11)]-2,3,3 &amp; 54555657,7 &amp;- Octahydroindole_2-carboxylic acid; [2 (8), 3 &amp; (8), 7 &amp; (11)]-2,3,3 &amp;, 4,5,6,757 &amp; -octahydro 2-Weird acid; and [2 (R), 3a (R), 7a (S)]-2,3,3a, 4,5,6,7,7a-octahydropi bow | σ 朵 魏 43 200303748 玖2. Description of the invention Acid or a pharmaceutically acceptable salt thereof. Another specific embodiment of the present invention is: 169. A method for preventing cartilage damage in lactating mammals, comprising administering to the mammal a therapeutically effective amount of aminomethylfolate and-selected from the following 5 compounds Combination: Gang, 3)), 7 Lu 2,3, from 5,6,7,7 ^ Hydroxy_2-chinic acid; [2 (Magic, 3_, 7La) Bu 253,3 &amp; 4,5 , 6,7,7 & octahydro + docolic acid; [2 (R), 3a (S), 7a (S)] _ 25353M, 556,7,7a &quot;LnM; [2 (S)? 3a (R) 57a (R)]. 253? 3a? 4? 5? 657? 7a., ViL ^ | ^ .2 ^ gi; 10 [2⑻, 3a⑻, 7a⑻ &gt; 2, 3, 3M, 5, 6, 7, 7α- Octahydro. Attractive _ Wei acid; [2 (R), 3a (S), 7a (R)] _ 2,353a5455,6,7,7a-octahydroindole_2_retemic acid; [2 (8) , 3 &amp; (8), 7 汪 (11)]-2,3,3 &amp;, 4,5,6,7,7 &amp; -octahydro 1 ^ voc_2_wei acid; and [2 (R), 3a (R), 7a (S)]-2,3,3a, 4,5,6,7,7a-octahydro "Gongbudo · 2_ ^ acid or a pharmaceutically acceptable salt thereof. 15 of the present invention Another specific embodiment is: 170. A method of treating osteoarthritis in a mammal, comprising administering to the mammal a combination of a therapeutically effective amount of aminomethylfolate and a compound selected from the group consisting of: [ 2 (8), 3 & am p; (8), 7 &amp; (8)]-2,3,3 &amp;, 4,5,6,7,7 &amp; -octahydro 5 丨 ^^ 2-carboxylic acid; 20 [2 (1〇, 3 & amp (11), 7 mad (1〇) -2,3,33,4,5,6,7,7 &amp; -octahydro 11 bow | Hou 1 carboxylic acid; [2 (11), 3 &amp; (8) , 7 &amp; (8)]-2,3,3 &amp;, 4,5,657,7 &amp; -octahydrocall | Hou_2-carboxylic acid; [2 (8), 3 &amp; (11), 7 &amp; (11) ] -2,3,3 &amp;, 4,5,6,7,7 &amp; -octahydro 11 induces _2-weilic acid; [2 (S), 3a (R), 7a (S)]-2, 3,3a, 4,5,6,7,7a-octahydroindole · 2-carboxylic acid; (2 (to), 3 &amp; (8), 7 &amp; (11))-2,3,3 &amp;, 4,5,6,757 &amp; -octahydroindole_2-carboxylic acid; 44 200303748 玖, description of the invention [2 (8), 3 &amp; (8), 7 (11)]-2,3,3 &amp;, 4,5,6,7,7 &amp; -octahydro $ | Hou (_2-Weic acid; and [2 (R), 3a (R), 7a (S)]-2,3,3a, 4,5, 6,7,7a-octahydropi bow | πDo · 2-acid acid or a pharmaceutically acceptable salt thereof. Another specific embodiment of the present invention is: 5 171. A method for preventing osteoarthritis in mammals, comprising administering a therapeutically effective amount of aminomethylfolate to a mammal selected from the group consisting of the following compounds : [2 (8) 53 &amp; (8), 7 &amp; (8)]-2,3,3 &amp;, 4,5,6,7,7 &amp; -octahydro ^ bow 丨 13 flowers_2-weilic acid; [2 (foot), 3 & (1 ^), 7 &amp; (1 ^)]-2,3; &gt; 3 &amp;, 4,5,6,7,7 &amp; -octachloro. Bow | 0 朵 _2_traiter acid; [2 (1 ^) '3 &amp; (8), 7 & (8)]-2,3,3 &amp;, 4,5,6,7,7 &amp; -octahydro卩 弓 卜 朵 _2-wei acid; [2 (8), 3mad (11); &gt; 7 & (11)]-2,3,3 &amp;, 4,5,6,7,7 &amp; -eight Hydrogen 11 induces vocabulary_2 &gt; _Rebel acid: [2 (8), 3 mad (11) '7 &amp;(8)]-2;) 3,3 &amp;, 4,5,6,7,7 &amp; -eight Hydrogen 13 leads to 11-2-acid acids; [2 (^ 0,3 &amp; (8), 7 &amp; (11)]-2,3,3 &amp;, 4,5,6,7,7 & -octahydro 11 lead 11 flowers _2-acid; [2 (8), 3 Zhuang (8), 7 & (11)]-2,3,3 &amp;, 4,5,6,7,7 &amp; -octahydro 11 Bow | Voice 1 &gt; &gt; 2-Amino acid; and [2 (R), 3a (R), 7a (S)]-2,3,3a, 4,5,6,7,7a-octahydroπ bow丨 Hou_2-acid acid or a pharmaceutically acceptable salt thereof. Another specific embodiment of the present invention is: 172.-A method for alleviating pain in a mammal, comprising administering to the mammal a therapeutically effective amount of Combination of aminomethylfolate and a compound selected from the following compounds: [2 (S)? 3a (S) 57a (S)]-2? 3? 3a? 455? 6? 7? 7a-y \ ; [2 (R), 3a (R), 7a (R)]-2,3,3a, 4,5,6,7 [2 (R) 53a (S) 57a (S)]-253? 3a545556? 7? 7a-A; [2 (S) 3a (R) Ja (R)]. 2 ^? 3M? 5? 6JJa ^ va〇? I ^ 45 200303748 玖, description of the invention [2 (8), 3 &amp; ( 11), 7 &amp; (8)]-2,3,3 &amp; 5455,657,7 &amp; -octahydroindole-2-carboxylic acid; [2 (1〇, 3 &amp; (8), 78 (1〇) -2, 3,3 &amp;, 4,5,6,7,73-octahydroindole-2-carboxylic acid; [2 (8), 3 &amp; (8), 7 &amp; (11)]-2,3,3 &amp; , 4,55657,7 &amp; -octahydroindole-2-carboxylic acid; and [2 (R), 3a (R), 7a (S)]-2, 3, 3a, 4, 5, 6, 7, 7a-octahydroindole. Duo-2-Jun 5 acid or a pharmaceutically acceptable salt thereof. Another specific embodiment of the present invention is: 173 · —a pharmaceutical composition comprising an aminomethylfolate and an optional From the following compounds: [2 (8), 33 (8), 73 (8)]-2,3,33,4,5,6,7,7 &amp; -octahydroindole-2-carboxylic acid; 10 [2 (1〇, 3 &amp; (1〇57 &amp; (11)]-2,3,33,4,5,6,7,7 &amp; -octahydroindole_2_metanoic acid; [2 (11 ), 3 &amp; (8), 7 &amp; (8)]-2,3,3 &amp;, 455,6,757-octahydroindole_2_carboxylic acid: [2 (3), 3 &amp; (Chem.) 57 &amp; (Phantom) -2,3,3 &amp;, 4,5,6,7,7 &amp; -octahydroindole. 2-carboxylic acid; [2 (8), 3 &amp; (11) 3 (8)]-2 , 3,3 &amp;, 4,5,6,7,7 &amp; -octahydro, indole-2_metanoic acid; [2 (1〇, 3Try 8), 7 & (11)]-2,3,3 ^ 4,5,6,7,73-octahydroindole_2_metanoic acid; 15 [2 (8), 3 &amp; (8), 7 & (11)]-2,3533,4,5,6,757 & -Octahydro Indole_2_weilic acid; and [2 (R) 53a (R), 7a (S) &gt; 2,3,3a, 4,5,657,7a-octahydropyridine, or 0-2 quinic acid or its medicine Together with a pharmaceutically acceptable carrier, diluent or excipient. Embodiment 3 20 Detailed Description of Preferred Embodiments The present invention provides a method for preventing or inhibiting cartilage damage in mammals, which comprises administering an effective amount of cartilage damage inhibiting 2,3,3a, 4,5,6, 7,7a-octahydroindole-2-carboxylic acid or a pharmaceutically acceptable salt thereof. The present invention also provides a pharmaceutical composition comprising 46 200303748 玖, invention description 2,3,3a, 4,5,6,7,7a. A A ah_2_ thin line second: medically acceptable Contains ... a method of preventing or treating osteoarthritis in mammals, and administering a therapeutically effective amount of 2: 4; a method comprising 5 ", M salts. The present invention also provides a method of relieving lactation pain A method comprising administering a therapeutically effective species to a pharmaceutically acceptable salt thereof. The composition of the present invention 'comprises _2,3,33,4,5,6,7, ^ octahydro # 2 carboxylic acid Or a pharmaceutically acceptable salt thereof, and 10 15 20 = _ agent. The present invention also provides a kind of 2,3 = ^ Lai or a mixture thereof. The present invention also provides a combination of valdecoxib and 2,3,3m, 5,6,7, w_ ^ acid or a pharmaceutically acceptable salt thereof, a pharmaceutical composition comprising the combination, and a method of using the combination. The invention also provides a combination of etanercept ",, 5,6,7,73" \ hydrogenate_2_metanoic acid or a pharmaceutically acceptable salt thereof, a pharmaceutical composition comprising the combination, and the The method of using the combination I. The invention also provides an Inflix maple with a '7a octahydroindole-2-carboxylic acid or a pharmaceutically acceptable salt thereof. 帛 A pharmaceutical composition comprising the combination and a combination thereof Method of use: The present invention also provides a combination of an aminomethylfolic acid and 2,3,3M, 5,6,7,7a-acid or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising the combination And how to use the combination. The compounds used in the method of Benmemin can further form a medicinal dish, which includes (but is not limited to) acid addition and / or salt testing 47 200303748 发明, invention description-Wen addition salt can be tested Compounds are formed, however base addition salts can be formed from acidic compounds. All of these forms are within the scope of compounds useful in the method of the invention. Pharmaceutically acceptable acid 5-addition salts of compounds useful in the method of the present invention include those derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, stone curcuma, hydrobromic acid, hydroiodic acid, hydrofluoric acid , Phosphorous acid and the like) non-toxic salts, likewise it can be derived from organic acids (such as aliphatic mono- and mono-acids, phenyl-substituted alkanoates, hydroxyalkanoates, alkanedioic acids, Aromatic acids, aliphatic and aromatic sulfonic acids, etc.) 10 non-toxic salts. Therefore, these salts may include sulfate, pyrosulfate, thiosulfate underhydrogen, sulfite, bisulfite, nitrate, phosphate, monohydrogenate, dihydrogen phosphate, metaphosphate Salt, pyrophosphate, gaseous, bromide, dish, acetate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberine Acid salt, dec 15-acid salt, fumarate salt, maleic acid salt, mandelate salt, benzamidine salt, chlorobenzoate, methylbenzoate, dinitrobenzene Formates, ugly salts, stupid salts, tosylate, phenylacetate, citrate, lactate, malate, tartrate, mesylate and the like. Amino acid salts such as arginine salts and their analogs, as well as grape 20 gluconate, galacturonate (see, e.g., Berge SM et al.'i, pharmaceutically acceptable salts are also contemplated. (Pharmaceutical Salts) ,, J. Pharma. Sci., 1977, 66: 1). Acid addition salts of compounds useful in the method of the present invention can be accomplished in a conventional manner by contacting the free acid form of the compound with a sufficient amount of the desired acid 48 200303748 玖, description of the invention to produce a non-toxic salt preparation. The free acid form of the compound can be reproduced by contacting the acid addition salt thus formed with a base, and separating the free acid form of the compound in a conventional manner. The free acid forms of the compounds prepared according to the method of the present invention differ slightly from their respective acid addition salts 5 in certain physical properties such as solubility, crystalline structure, hygroscopicity and the like, but In addition, the free acid forms of these compounds and their respective acid addition salt forms are equivalent for the purposes of the present invention. A pharmaceutically acceptable base 10 addition salt of a compound useful in the method of the present invention can be obtained by combining the free acid form of the compound with a non-toxic metal cation such as an alkali gold or alkaline earth metal cation, or an amine (in particular Organic amines)). Examples of suitable metal cations include sodium cations (Na +), potassium cations (K +), magnesium cations (Mg2—), calcium cations (Ca2 +), and the like. Examples of suitable amines are N, N, · bisbenzylethylene diamine, gas procaine 15, choline amine, diethanolamine, dicyclohexylamine, ethylenediamine, N-methyl reducing glucose and Procaine (see 'for example, previous Berger, 1977). Base addition salts of the compounds useful in the method of the present invention can be prepared in a conventional manner by contacting the free acid form of the compound with a sufficient amount of the desired base to produce a salt. The free acid form of the compound can be reproduced by contacting the salt form formed as described above with an acid, and the free acid of the compound can be isolated in a conventional manner. The free acid form of a compound useful in the method of the present invention differs slightly from its respective salt form in certain physical properties such as solubility, positive structure, hygroscopicity and the like, but otherwise, These salts are equivalent to the respective free acids 49 200303748 and the invention description for the purpose of the present invention. Compounds useful in the method of the invention can exist in unsolvated and solvated forms, including hydrated forms. In general, the t-form (including the hydrated form) is the same as the unsolvated form, and is intended to be included within the scope of the present invention. Compounds useful in the methods of the invention may possess one or more palm centers, each center may exist in a ruler or 8 structure. The method of the present invention can use any non-mirror isomers, mirrors, or 2,3,3a, 4,5,6,7,7a-octahydroindole-2 · carboxylic acid or a pharmaceutically acceptable salt thereof, or Epimeric form, and its 10 mixture. The methods described herein can also use isotope-labeled compounds that are the same as those described above, but in fact they have one or more atoms that differ from one that has an atomic weight or mass number that is usually found in nature. Atom replacement. Examples of isotopes that can be incorporated into the 15 compounds used in the method of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as 2Η, 3Η, 13c, 14c, 15ν, 18. , 170, ρ, P, s, 18F and 36C1. Isotopic compounds containing the aforementioned isotopes and / or other atoms and pharmaceutically acceptable salts of the compounds used in the method of the present invention are within the scope of the present invention. 20 Certain isotopically labeled compounds used in the present invention (such as those that have been incorporated with radioisotopes such as 3h and 14C) can be usefully used in medicine and / or matrix tissue distribution tests. Thallium (ie, 3H) and carbon · 14 (ie, &quot; C) isotopes are particularly good for their easy preparation and detection capabilities. Furthermore, replacement with heavier isotopes such as deuterium (ie, 2h) can obtain some of the therapeutic advantages resulting from the larger new 50 200303748 tritium, invention description 5 metabolic stability, such as its increased life span Or reduce the need for dosage, so it is better in vivo in some cases. The isotope-labeled compounds described above in the present invention can generally be obtained by performing the procedures described above and below by reference, or disclosed in the following diagrams and / or examples and injection materials (if any). It can be prepared by replacing a non-isotopically labeled reagent by using an easily available isotopically labeled reagent. The compound useful in the method of the present invention can also be used in combination with a therapeutic agent having osteoarthritis. Suitable 10 agents to be used in the combination include standard non-steroidal anti-inflammatory drugs (nsaid's thereafter), such as piroxithine, diphenfenic acid; propionic acids, such as fenprofenac, fluorobiphenyl Propionic acid, phenoxyphenylpropionic acid, phenone phenylpropionic acid, and isobutyrylpropionic acid; fenamates, such as mefenamic acid, indomethacin, sulindac, inflammation Apazone; pyridazolones, such as phenylbutazone; salicylates, such as aspirin; COX-2 inhibitors, such as celecoxib ) And rofecoxib; analgesics and intra-articular treatments, such as corticosteroids and glauronic acids, such as hyalgan and synvisc. The invention also relates to a method for treating inflammation A method or pharmaceutical composition of a process and disease comprising administering a compound useful in the method of the invention to a mammal (including human, jute, livestock or dog), wherein the inflammatory process and disease are as defined above, The inhibitor compound can be combined with one or more other treatments. Active agent combination, and used in the following symptoms: 51 200303748 发明, description of the invention 9) If the joint has become severely inflamed and infected by bacteria, fungi, protists and / or viruses' The inhibitor combination can be combined with- Multiple medicaments, anti-drug agents, protozoal agents and / or antiviral therapeutic drugs are administered in combination; / ·) If multiple treatments for pain and inflammation are desired, the inhibitor combination can be inhibited with its inflammatory mediator The combination of the agents, the inhibition of the other inflammatory mediators may comprise one or more groups independently selected from the group consisting essentially of: (1) NSAIDs; (2) H-receptor antagonists Class; (3) kallikrein- and By receptor antagonists; glibrestinin inhibitors, which may be selected from the group consisting of pGD ·, pGF_pGl2 ·, and PGE-receptor antagonists; (5) ) ¾¾ amine a2 (txa2_) inhibitor; (6) 5-, 12- and 15-lipoxygenase inhibitors; (7) leukotriene LTC4-, LTD4 / LTE4- and LTB4- inhibitors (8) PAF-receptor antagonists; (9) gold, which is in the form of a gold sulfur group together with one or more hydrophilic groups ; (10) immunosuppressives, which may be selected from the group consisting of cyclosporine, azathioprine, and aminomethylfolate; (11) anti-inflammatory glucocorticoids; (12) penicillamine (13) Hydroxychloroarsine; 52 200303748 玖, description of the invention (14) anti-gout agents, including colchicine; xanthine oxidase inhibitors, including allopurinol; and diuretics, which can be selected from Probenecid, bensulfazone and benzbromocoumarin; C ·) if used to treat symptoms of disease in older mammals (complications and symptoms found in older 5 mammals), The inhibitor combination may be administered in combination with one or more groups each independently selected from the group consisting essentially of: (1) cognitive therapy to combat memory loss and impairment; (2) antihypertensive and Other cardiovascular drugs intended to compensate for the results of arteriosclerosis, hypertension, cardiac ischemia, angina pectoris, congestive heart failure, and myocardial infarction can be selected from the group consisting of: a. Diuretics B. Vasodilators c-β-adrenaline-induced Antagonists; 15 d. Angiotensin-II conversion enzyme inhibitors (ACE-inhibitors), which can be used alone or selectively with neutral peptide inhibitors; e. Angiotensin II receptor Antagonists; f · renal hormone inhibitors; g · calcium channel blockers; 20 h · sympathetic agents; i adrenaline stimulants; j · adrenaline stimulants Receptor antagonists; and k.HMG-CoA-reductase inhibitors (anti-hypercholesterolemia); (3) Agents for preventing malignant tumors, which can be selected from the following: 53 200303748 发明, Description of invention a · Anti-mitotic music species, which can be selected from the following i. Vinca alkaloids, which can be selected from the following: [1] Vinblastine and, [2] Vincristine; 5 (4) Growth hormone promoting Secretory agents; (5) strong analgesics; (6) local and general anesthetics; and H2-receptor antagonists, proton pump inhibitors, and other stomach-protecting agents. 10) Compounds useful in the methods of the present invention may be administered in combination with inhibitors of other inflammatory mediators, the inhibitors of other inflammatory mediators comprising one or more members selected from the group consisting essentially of: The types of these inhibitors and their examples include: parent metalloproteinase inhibitors, polyprotein multi-material inhibitors, TACE inhibitors, leukotriene receptor antagonists, 15 to 1 treatment and release inhibitors, ILra , Hi_ receptor antagonists; Kallikrein-Br and By receptor antagonists; Prostaglandin inhibitors such as pGD_, PGF-PGIr and PGE-receptor antagonists; Thromboxamine A2 (τχΑ2_) inhibition Agents; 5- and 12-lipoxygenase inhibitors; leukotriene LTC4_, LTD4 / LTE4- and LTB4- inhibitors; PAF-receptor antagonists; MEK inhibitor 20 preparation; ΪΚΚ inhibitor; MKK inhibitor Gold, which is a form of gold sulfur groups together with different hydrophilic groups; immunosuppressants, such as cyclosporine, azathioprine, and aminomethylfolate; anti-inflammatory glucocorticoids; Penicillamine; Hydrochlorochloromethane; Anti-gout agents, such as colchicine Xanthine oxidase inhibitors, e.g., allopurinol; and diuretics, e.g. 54200303748 Nine described invention 'probenecid, sulfinpyrazone stupid bromo benzene and coumarone. The compounds useful in the method of the present invention can also be used in combination with the following anti-cancer agents such as endostatin and angiostatin; or cytotoxic drugs such as Adamycin 5 (dnamycin), daunomycin, aflatoxin, podophyllotoxe, taxol, taxotere; and bioassays such as Changchunxin Bases; and antimetabolites, such as aminomethylfolate. Compounds useful in the methods of the present invention may also be used in combination with the following agents: antihypertensive and other arteriosclerotic diseases intended to compensate for hypertension, including angina pectoris, congestive heart failure, and myocardial ischemia Cardiovascular drugs, which can be selected from vasodilators, such as hydrazine; β-adrenergic receptor antagonists, such as propranolol; calcium channel blockers, such as nylon Nifedipine; α2-adrenergic agonists, such as clonidine; α-adrenergic receptor antagonists, such as prazosin and HMG -CoA-reductase inhibitor (anti-hypercholesterolemia) 'such as 10 vastatin or atorvastatin. Compounds useful in the methods of the invention may also be combined with one or Multiple anti-20 halogens, anti-halotropic agents, protozoans, antivirals, or similar therapeutic drugs are administered in combination. Compounds useful in the methods of the present invention may also be used in combination with: CNS agents such as antidepressants (such as Sertraline); anti-Parkinson's drugs (such as levodopa ( L_ 55 200303748 玖, description of the invention dopa), reqUip, mirapex; MAOB inhibitors such as selagine and rasagiline; cornP inhibitors such as answer Tasmar; Ad inhibitors; Dopamine reuptake inhibitors; NMDA antagonists; Nicotine synergistic agents; Dopamine synergistic 5 agents; and neuronal nitric oxide synthase inhibitors) and anti-ar 'Zeuheimer's disease fun things' such as donepezii, tacrine, COX-2 inhibitors, propenopfylline, or Ma Fengfeng Leite (Metryfonate). Compounds useful in the method of the present invention can also be used in combination with the following agents: osteoporosis agents, such as roxifene, lasofoxifene, droxifene, or ephedrine Fosomax; and immunosuppressive agents, such as FK_506 and rapamycin. The present invention also relates to a 15 20 formulation of a compound useful in the method of the present invention, which may have a separate Compound or one or more other therapeutic drugs that can form a desired combination, the formulation may include different drugs with different half-lives, whereby a controlled release form of these drugs (which has a different release time and (Achieve fairly uniform dosing); or in actual injections in non-human patients, the drugs used in combination can be exchanged into the feed dosage form of the drug-existing in the feed composition mixture. What can be further provided according to the present invention is co-administration ... The combination of the drugs can be obtained by simultaneously administering the drugs to provide the combination; this includes co-administration by different dosage forms and routes of administration丨 Use this combination according to different but regular and continuous dosing schedules, by which 2003 200303748 发明, invention description can maintain the contained drugs to the desired level of blood pressure in patients to be treated (even if not at the same time The individual drugs that make up the combination are administered to the patient). The method of the present invention can be used in human and veterinary medicine to treat osteoarthritis or suppress cartilage damage in mammals, and can be used to treat any other diseases or disorders (where the cartilage damage is a symptom or contains: to be treated Of the basic symptoms).

The names and wording used herein are as defined below or may be defined as they appear in the patent specification. As for the wording "2,3,3 ^ 4,5,6,7,7 ^ octahydroindole-10 carboxylic acid" as used herein means a compound selected from the following: [2 (S), 3a (S), 7a (S)]-2,3,3a, 4,5,6,7,7a ~ \ | ^ nM; [2 (R), 3a (S), 7a (S)]-2 , 3,3a, 4,5,6,7,7a &quot; \ | ^ | n_; [2 (8; »(11), 7 &amp; (11)]-2,3,3 &amp;, 4,5,6 , 7,7 &amp; -octahydroindole_2-endanoic acid; 5 [2 (S) '3a⑻'7a⑻bu 2,3'3a, 4,5,6,7,7a-octahydroindura-2- Acid

[2 (11), 3 &amp;(8; »(11)]-2,3,3 &amp;, 4,5,6,7,7 &amp; _octahydroindole_2-metanoic acid; [2 (8) , 3 &amp; (8), 7 &amp; (to)]-2,3,3 &amp;, 4,5,6,7,7 &amp; -octahydroindole_2 side acid; and [2 (R), 3a ( R), 7a (S)]-2,3,3a, 4,5,6,7,7a-octahydrotendosuccinic acid. 20 For the purpose of clarification, named [2 (8), 348), 7α (8)] · 2,3,3 &amp;, 4, 5,6,7,7a-octahydroindole-2-carboxylic acid compound has the structure drawn in the following:

200303748 发明, description of the invention named [2 (11), 3 &amp; (11), 7411)]-2,3,3 &amp;, 4,5,6,757 &amp; -octahydroindole- 2-carboxylic acid compound Has the structure drawn in:

It should be understood that the 2,3,38,4,5,6,7,7 &amp; -octahydroindane 13-ring system uses 5 the following numbering methods:

The name "etanercept" means a dimeric molten protein composed of a human 75-kilogram ear ("p75,") tumor necrosis factor receptor ("TNFR") linked to the Fc portion of human IgG1. ) Of the extracellular ligand binding part. 10 The Fc component of etanercept includes a Ch2 segment, a CH3 segment, and a drug-containing region, but a CH1 segment without IgG1. Etanercept can be manufactured in the Chinese hamster ovary ("CHO") mammalian cell expression system by recombinant DNA technology. It consists of 934 amino acids and has an apparent molecular weight of about 150 kilotons. Etanercept is a tumor suppressor 15 (TNFTNF) inhibitor. Etanercept is sold in the United States under the trade name ENBREL (R) and is used to treat rheumatoid arthritis and arthritis psoriasis. Amber is provided as a sterile, white, preservative-free, lyophilized powder in 20 μl of sterile sterile water for injection (USp (including 0.90 / 0 benzyl alcohol)) supplied at 1 liter. It can be used for parenteral administration. After recovery, Amber's solution was transparent 58 200303748 玖, the invention description was clear and colorless, ρΗ7.4 · 0.3. A single vial of Amber contains 25 mg of etanercept, 40 mg of mannitol, 10 mg of sucrose, and 1.2 mg of tromethamine. The name "Inflix Mapper," includes products sold in the United States under the trade name REMICADE⑧, which can be used to treat rheumatoid arthritis / r. Inflammation. Name "Aminomethyl Folic acid, including a compound named N_ [4 _ [[(2,4_Diaminopteridinyl) methyl] methylamino] benzylidene] _L_glutamic acid or a pharmaceutically acceptable compound thereof salt. Aminomethylfolate can be used to treat certain neoplastic diseases, severe psoriasis, and adult rheumatoid arthritis. For example, sodium aminofolic acid lozenges for oral administration can be obtained in a packaging system labeled RHEUMATREX® sodium aminofolic acid sodium dosing, which uses 5 g, 7 g 5 mg, 10 mg, 12.5 mg, and 15 mg of the parental methyl folic acid schedule for treatment, and 15 of the following medicines acceptable excipients, diluents or carriers · lactose, hard Magnesium stearate and pre-gelatinized starch. The lozenges may also include corn flour. Aminomethylfolate can also be administered by intramuscular, intravenous, intraarterial or intrathecal injection. The name "valdecoxib," means the compound named 4 · (5_methyl_3 • phenyl-4_ /, fluorenyl) -benzite. The valdecoxib has a structure drawn in the following 20 columns: 59 200303748 发明, description of invention

Vardecoxib is a specific epoxy peak-2 ("COX-2") inhibitor. It is approved by the US Food and Drug Administration ("FDA") for oral treatment of bone inflammation and adult rheumatism. Signs and symptoms of osteoarthritis; and treatment of pain associated with menstrual cramps. In addition, vardecoxib can be used in clinical trials to treat migraine & gastric and vaginal coloxib tablets are exported under the trade name BEXTRA⑧. In a combined analysis of various clinical studies using vardecoxib, Λ vardecoxib has significantly improved the overall upper gastrointestinal ("GI") safety status (ulcers, penetrating obstruction, and GI exudation) compared to the known 10 15 Studies of NSAIDs (Tan '丁 丁 # ^ 呷 九 (such as isobutyrylpropionate, diphenfenac, and oxynaphthopropionate) are quite well tolerated. It should be understood that the two forms are now well known Cyclooxygenase ("c0x"), in other words-usually named as epoxy epoxizine] ("_ ,,) is an isomeric form of the constituent molecule and one is usually named wangxin oxygen qi_2 (" cox_2 "), An isoform induced by the latter, which is expressed upregulated at the position of pi mu 叽 叽 发 发 。. COX-1 appears to play a physiological role and respond to gastrointestinal and renal protection. Another -On the one hand, ⑶χ_2 appears to play a pathological angle, and Xianxin appears to be the dominant isoform in inflammatory symptoms. Conventional COX inhibitors (typically coti and both 60 200303748) 玖And non-selective inhibitors described in the invention) The pathway is limited due to medical-related side effects, including life-threatening cancer ulcers and kidney toxicity. Compounds that selectively inhibit COX-2 will exert anti-inflammatory effects without the negative side effects associated with cox] inhibition. 5 When The name "mixture" used in the specific embodiments described in the context of the present invention refers to two or more 2,3,3 ^ 4,5,6,7,7 octahydroindole-2_carboxylic acids or Each of them independently selects a pharmaceutically acceptable salt, and may include a racemic mixture of mirror images, a non-racemic mixture of mirror images, which includes a mirror image containing from 0.0001% to 99.9999% and 10 99.9999% to 0.0000 / 00/0 of another mirror image mixture, in which 2,3,3 &amp;, 4,5,6,7,7 &amp; -octahydroindole_2-carboxylic acid The total amount is 100%; and the mixture of non-mirror isomers includes a non-mirror isomer containing from 0.001% to 99,999% and, conversely, from 99,999% to 0.001%. Another mixture of non-mirromeric isomers, in which the total amount of 2,3,3 ^ 4,5,6,7,7 octahydroindole_2_ 15 carboxylic acid is 100%. It should be understood The names "uses,", "utilizes," and "employs" and their derivatives can be used interchangeably to illustrate specific embodiments of the invention. The name "drugs," includes 2 , 3,3a, 4,5,6,7,7a-Octaazepine_2_metanoic acid or a pharmaceutically acceptable salt thereof, which may further include one or two other therapeutic drugs described above. Name ΕΕ &gt; 4 ( &gt; Means—a medicinal dose containing 2,3,3M, 5,6,7,7a · Hydroxy-2-carboxylic acid or a pharmaceutically acceptable salt thereof, which is at least in patients to be treated 40% is sufficient to inhibit cartilage damage or to treat a disease or condition listed in 61 200303748, the invention description. "% Of patients" means mammals. 5 10 15 20 For the purposes of the present invention, the names "Breastfeeding and mobilization 1 and dogs", livestock animals rabbits: two sheep type W) and laboratory animals (Such as guinea pigs, squirrels, hamsters, and monkeys), and genetic variants. / Saying "Companion animals, including dogs, I seedlings, rabbits, warehouses, monkeys, horses, and other domestic or barn pets. 'For example: the phrase" livestock animals, 'Refers to the four legs that are left over. Class 'which includes those used in breeding, · Han + Putian 彳 products, such as family animals' includes cattle and other members of the genus Boar; pig family domesticated pigs and others_ 成 贞 ^ Μ ^ «Ping Animals, including sheep and other sheep of the genus Shepherd; domesticated goats and their M, mountain genus of shellfish; domesticated tetrapods used to solve special work (^ ^ ^ X is used as weight-bearing animals), For example, equine animals, including domesticated horse cheeks and members of the genus Dacidae, Equus; or for searching and guarding tasks, such as ^ Kangidae, including domesticated dogs, members of the Canine genus; And 1,11 breeds are mainly used to solve the quadrupeds for leisure purposes: members, examples # 'Equus and canine members, and judas include the %% and other feline and feline members. The purpose of Mao Yue's brother is to name 'arthritis, including osteoarthritis'. = Arthritis, joint degenerative disease, spinal joint disease, gouty fire, systemic lupus erythematosus, juvenile arthritis and psoriasis Bone Disease of Joint Moxibustion 0 Words "Cartilage ㈣, means 箸 transparent Bone and subchondral 62 200303748 发明, description of the invention 'characterized by hypertrophy of tissues in and around the joints involved, which may or may not be accompanied by damage to the surface of hyaline cartilage. The wording "inhibit cartilage damage," means The therapeutic effects of the compounds or combinations defined above can inhibit the development of any one or more of the observed symptoms of cartilage damage for any disease or condition that has cartilage damage as a component of the disease or disorder condition Development or reversibility (partial or full). ίο 15 20 The wording "an effective amount for inhibiting cartilage damage" means an amount or amount sufficient to inhibit the development of symptoms of cartilage damage in any one or more of the patients that are known or suspected or expected to be treated, Prevents its further development or reverses its development (in part or in whole). The word "treatment" means the administration of one or more compounds or combinations which, according to the method of the invention as defined above, can inhibit any one or more pathologies The development of features or symptoms of any one of the diseases and conditions to be treated, including (but not limited to) cartilage damage, pain and inflammatory symptoms, preventing their further development or reversing their development (partially or fully). The wording "treat bone Arthritis, meaning the administration of one or more compounds or combinations' according to the invention, as defined above, can inhibit any one or more symptoms of osteoarthritis (including, but not limited to) cartilage damage, pain and inflammation Symptoms), prevent their further development-or may reverse some or all of them). Stop the onset of symptoms' or inhibit any of the expressions "prevent," meaning that a patient is given one or more compounds or a combination of symptoms, according to the present invention, as defined above, which inhibits 6363 200303748 发明, description of the invention γ stop any one or more pathological features of the disease and disorder, prevent its further development or reverse its development (partial or all). 彡 "said Pfang only cartilage damage, 'I Said to administer one or more compounds or 15 to asymptomatic patients' according to the method of the present invention as defined above, 5 can inhibit the initial symptoms to be prevented, or _ can inhibit one or more cartilage once it has started to occur The development of the pathological characteristics of the injury, preventing its further development or reversing its development (in part or in whole). The wording "prevent osteoarthritis," which means administering one or more compounds or combinations to asymptomatic patients, according to the method of the present invention as defined above, and which can suppress the initial symptoms to be prevented, or-once Onset can inhibit the development of any one or more of the pathological features of osteoarthritis, prevent further development of the pelvis or reverse (part or all) its development. /, The wording "relieves pain," meaning one or more compounds Or combined effect, according to the method of the present invention as defined above, which can inhibit, reduce, prevent, or otherwise inhibit a patient's pain, including (but not limited to) inhibiting, reducing, preventing, or inhibiting due to cartilage Pain symptoms of injury, inflammatory pain, and pain associated with autoimmune disorders. It should be understood that the method of the present invention is used preventively to prevent or suppress the onset of osteoarthritis and cartilage damage in mammals. Mammals in need of prophylactic treatment in particular can easily be identified by those skilled in medical and medical techniques ′ by assessing certain risk factors related to the particular symptoms to be prevented. These risk factors include the family history of the patient's cartilage damage or osteoarthritis, the need to participate in sports or other physical activities (such as woodworking, casting operations, and the like), and genetic risk factors. 64 200303748 i. Description of the invention The words "therapeutically effective amount," and "effective amount," are synonymous and mean an amount of a compound or combination as described above, which is sufficient to inhibit any one or more of the particular patients to be treated The development of symptoms of a disease or disorder that are known or suspected or anticipated, prevent its further development or can reverse its development (partially or fully). For the treatment of osteoarthritis or inhibition of cartilage damage according to the method of the invention, Decided that the treatment consisting of 253,3 &amp;, 455,6,7,73-octahydroindole-2-carboxylic acid or a pharmaceutically acceptable salt thereof (or a combination thereof with vardecoxib) has a long history ^ The therapist or veterinarian will generally take into account a number of factors in light of the medical person's or veterinarian's, 10 published clinical research experience: the subject's (ie, mammal) age, sex, weight, and general conditions, and the The type and extent of the disease, condition or symptom, and other medications, if any, used by the patient. This amount is usually from about 0.01 mg / kg to about 300 g / kg of the patient's weight For the normal weight of an adult patient, the dose of canonical type 15 will be from about 10 to about 5,000 mg / day. In clinical settings, regulatory agencies such as, for example, the FDA in the United States, will require a specific therapeutically effective amount As such, the administered dose may fall within the range or amount described above or may vary outside of that range (ie, below or above), and those ranges may depend on the needs of individual patients and the symptoms to be treated. Depending on the severity and the particular 20 treatment formula used. Those familiar with medical or veterinary techniques can determine the appropriate dose for a particular situation. Generally speaking, treatment can be started with a smaller dose (which is less than optimal for that particular patient) Amount) of 2,3,3M, 5,6,7 ▲ Octaazepine · 2-Junic acid or its pharmaceutically acceptable salt (or its combination with vardecoxib) is started. After that, the dose can be small The method of increase is increased until 65 200303748 can be completed. The invention illustrates the most ideal effect. For convenience, the total daily dose can be divided into several parts during the period. Medicine 2,3,3m, 5,1: or Medically acceptable salts (or their combination with vardecoxib) are used to 'the drug can be formulated alone or in a toiletry preparation into a combination suitable for pharmaceutical administration ..., 6,7,7a_octahydro Catch 2_Gunic Acid or a pharmaceutically acceptable salt thereof: Musical composition (which is briefly described here and is more fully described below) :: By formulating the active compound in a dosage unit containing a pharmaceutical carrier ίο = Examples of certain dosage unit forms are lozenges, capsules, capsules, aqueous and non-aqueous oral solutions and suspensions, and enteric solutions (which contain-one or -some) enclosed in :: Larger doses can be subdivided into early doses and can be subdivided into individual doses.) 15 20 Some examples of suitable pharmaceutical carriers (including pharmaceutical diluents) are gelatin gum heavy sugars, such as lactose and tincture; dian powder, such as jade Grape flour and glutinous rice flour; cellulose derivatives, such as sodium methyl cellulose, ethyl cellulose, methyl cellulose, and vinegar delta cellulose; gelatin; talc; stearic acid; stearic acid Acid town '· Vegetable oils, such as peanut oil, cottonseed oil, sesame oil Satu! Oil, Corn germ oil and cocoa butter; propylene glycol, glycerol; sorbose, acetobacter, water; fat breaking; alginic acid; isotonic saline and dish acid buffer solution; and other normal use in pharmaceutical formulas Compatible substance. The composition to be used in the present invention may also contain other components such as a colorant, a flavoring agent and / or a preservative. These substances, if present, are usually used in relatively small amounts. The composition may also contain other therapeutic agents commonly used for the treatment of osteoarthritis, if necessary. Furthermore, if necessary, the composition 66 200303748 ii. Description of the invention It may contain other therapeutic drugs that are generally used to treat secondary symptoms such as, for example, inflammation or pain that may or may not be accompanied by cartilage damage. For example, these compositions may include aspirin, menacin or similar anti-inflammatory analgesics. 5 The percentage of active ingredients of the foregoing composition may vary within wide limits, but for practical purposes it is preferably present at a concentration of at least 10% of the solid composition and at least 2% of the main liquid composition . The most satisfactory compositions are those in which a higher proportion of active ingredients are present (e.g., up to about 95%). 1〇2'3'3 &amp;, 4,5,6,7,7 Preferred administration of octahydroindole-2-carboxylic acid or a pharmaceutically acceptable salt thereof (or a combination thereof with vardecoxib) The route is oral or parenteral. For example, a useful intravenous dose is 5 to 50 mg and a useful oral dose is 20 to 800 mg. This dose is within the range of administration used to treat diseases caused by cartilage damage, such as osteoarthritis, or may be determined by the physician based on the needs of the patient as described above. 2,3,3 &amp;, 4,5,6,7,7 &amp; -octahydroindole-2-carboxylic acid or a pharmaceutically acceptable hydrazone (or a combination thereof with vardecoxib) can be administered in any form. The blister is preferably in the form of a unit dose. The 2,353M, 556, 7Ja-octahydro, bow !, flower | unit acid or a pharmaceutically acceptable salt thereof intended to be used in the unit dosage form of the present invention may also contain other substances that are caused by cartilage damage Disease-useful compounds. It is easy to prepare and in fact the compounds are reasonably well tolerated, and IV and oral administration of these drugs is easy. Furthermore, 67 200303748 (ii) Description of the invention These compounds typically do not cause metabolism in the body. Another important advantage is that 2,3,33,4,5,6,7,7 &amp; -indolin-2-carboxylic acids can provide bone inflammation and other diseases with cartilage damage as a component of the disease And illness disease modification activity 5. Currently, there are no identifying drugs on the market that can be used for this activity. Furthermore, the present invention allows, if necessary, to reduce or even eliminate the dosage of anti-inflammatory agents and / or pain-reducing agents used to treat patients suffering from cartilage damage and inflammation and / or pain. These anti-inflammatory and analgesics are known to cause unwanted side effects such as gastrointestinal bleeding and ulcers. These side effects can be avoided, reduced or eliminated by using the present invention to inhibit cartilage damage. For synthesizing 2,3,3a, 4,5,6,7,7a-octahydroindole-2-carboxylic acid or a pharmaceutically acceptable salt thereof useful in the method of the present invention and a pharmaceutically acceptable The intermediates of salts can be prepared by those who are familiar with organic chemistry techniques using different synthetic procedures which are quite well known in organic chemistry techniques. These synthetic procedures can be found in the literature. For example, the following will list a few: organic synthesis reagents (heart agwh / m OgamY 5 &gt; valence / ^), by Fieser and Fieser 'John Wiley &amp; Sons, Inc., New York, 2000; Comprehensive Organic Transformations 20, you can check Richard C. Larock, VCH VCH Publishers Inc., New York, 1989; An Introduction to Organic Synthesis Methods, Factory Customized Price Series, 1989, by Wiley-Interscience; Advanced Organic Chemistry (ddv⑽eed 68 200303748)发明 Description of invention

Orgam'c CT2㈣⑻r ;;) Textbook, 4th edition, by Jerry March, Wiley-Science, New York, 1992; or Handbook of Heterocyclic Chemistry »by Alan R. Alan R. Katritzky, Pergamon 5 Press Ltd., London, 1985. In addition, those skilled in the art can find useful methods for preparing intermediates in the chemical literature by extensively searching available databases, such as, for example, from the Chemical Abstracts Service (CTzem / co / J ~ iraek Serv / ce), Columbus, Ohio; or those obtained by MDL Information System GMBH (MDZ Earlier 10 Bielstein Information System GmbH / w / brmaiz · ⑽, Frankfurt, Germany. Useful in the method of the present invention Compounds can be prepared using starting materials, reagents, solvents, and catalysts purchased from commercial sources, or they can be easily prepared by employing procedures in the references or resources cited above. 15 In preparing the compounds of the present invention Commercially useful starting materials, reagents, solvents, and catalysts include, for example, Yadefu Chemical Company (772e ”/ (irz * c / z C / zem / ca / and Sigma-Yadefu Co., Ltd.) (Sigma-Aldrich Corporation) 's other subsidiaries, St. Louis, Missouri, Bakken (5 "C // 5M), Bakken 20 AG, Switzerland, or Lancaster synthesis Limited company like / er office ni / zeszjjLe ·), the United Kingdom of Great Britain. The synthesis of certain compounds useful in the method of the present invention can use starting materials, intermediates or reaction products containing a reactive functional group During the chemical reaction, the reactive functional group can be protected with a protecting group that makes the anti-69 200303748 rose, the invention explains that the reactive group is substantially inert under the reaction conditions used. Protection is needed for For the group, the protecting group can be introduced into the starting material before the reaction step is carried out. Once the protecting group is no longer needed, the protecting group can be removed. A technique that is quite well known in the art is at 5 A protective group is introduced during the synthesis of 2,3,3 ^ 4,5,6,7,7 octahydroindole-2-carboxylic acid or a pharmaceutically acceptable salt thereof, and it is removed later. Use The procedures for introducing and removing protective groups are well known, and reference can be made to, for example, Protective Grunds in Organic Synthesis (Protective Gróups in ORganic), 2nd Edition, Greene Ding w. and Watts p G · John Willy 10 &amp; Sans New York: New York, 1991, which is incorporated herein by reference. Thus, for example, protecting groups such as the following may be used to protect amine groups, hydroxyl groups, and other groups... Ethylfluorenyl and trifluoroacetamyl; alkoxycarbonyl groups such as, for example, ethoxycarbonyl 'tertiary butoxycarbonyl (BOC), β, β, β-trifluoroethoxycarbonyl (but (^ (: ) And iodoethoxy 15 carbonyl, aryl oxycarbonyl, such as, for example, benzyloxycarboxyl (CBZ), p-methoxybenzyloxycarbonyl and 9-fluorenylmethoxycarbonyl (FMoc) Trialkylsilyl 'such as, for example, trimethylsilyl (TMS) and tertiary butyldimethylsilyl (TBDMS); and other groups such as, for example, triphenylmethyl (trityl ), Tetrahydropiperanyl, vinyloxycarbonyl, o-nitrophenylsulfinyl 20, monophenylphosphino, p-methylbenzylsulfonyl (Ts), methanesulfonyl, tris Formamyl and benzyl. Examples of procedures for removing protecting groups include hydrogenolysis of CBZ groups, which can use, for example, 50 psi hydrogen in the presence of a hydrogenation catalyst, such as 10% saturated / carbon; acid of Boc group It can be cleaved using, for example, hydrogenated gas in dichloromethane, trifluoroacetic acid 70 200303748 hydrazone in dichloromethane, description of invention (TFA) and the like to break the TCEC group. Silicon group reacts with fluoride ions; and reduction with zinc metal has useful 2,3,3a, 4,5,6,7,7a · octahydroind alpha alpha 2-carboxylic acid or its medicine The preparation of the salt that can be used for money is incorporated by reference in the patents or patent application announcements described above and below. Some preparations of '3a'4'5'6'7'7a-octahydroindolecarboxylic acids are described in U.S. Patent No. 4 6qi. ^, 691,022, 4,879,392; 4,914,214; 4,935,525 &gt; 4? 954 ? 640; 5 OOR αππ 5,008,400, 5,101,039; and 5,258,525, which are incorporated herein by reference. 1〇2'3,3a, 4,5,6,7,7a-octahydrokou bow | Hou · 2 · Jun acid other preparations are described in European Patent No. 0,037,231; 〇, 〇84,164; 〇, 115,345; 0,173,199 *, and 0,132,580, which are incorporated herein by reference. Other preparations of 2,3,3 &amp;, 4,5,6,7,7 &amp; -octahydroindole_2-carboxylic acids are described in Patent Cooperation Treaty ("PCT") Application Publication No. WO 93/13066 And 15 is incorporated herein by reference; and WO 00/40555, which is incorporated herein by reference. Another method of preparation is described in the Journal of Pharmaceutical Chemistry (Jbwrwa / 〇 / MWc— /), 1987; 30: 992-998, which is incorporated herein by reference. 2,3,3 &amp;, 4,5,6,7,7 &amp; -octahydroindole-2-carboxylic acid or a pharmaceutically acceptable salt thereof Recently found to inhibit cartilage damage, relieve pain and treat bones and joints Inflammatory capacity can be established in animal models described below. Biological Method 1 In a mouse model of cartilage damage ("MIA rat"), iodoacetic acid alone 71 200303748 发明, invention description steel-induced osteoarthritis: In this model, a final result of osteoarthritis (such as (Measured by histological analysis) is the development of osteoarthritis symptoms in the affected joints, and it is characterized by the loss of aniline blue staining and the formation of osteophytes. Related to the 5 histological changes is the concentration-dependent reduction of articular cartilage, as can be clearly understood from the effect on the weight distribution of the hind paw that includes the affected joint's foot, in biochemical analysis or histopathological analysis of bone and joint lesions Later, an increased amount of proteoglycan or hydroxyproline is shown in the joints. 2'3,3 &amp;, 4,5,6,7,7 &amp; -octahydroindole_2-carboxylic acid compounds or their pharmaceutically acceptable salts when used in acute models (such as immediate MIA mouse model) is not effective in alleviating pain when administered, and it only has a duration of 14 or 28 days. The observed effect of hind paw weight distribution is the following; or for 2,3,3 &amp;, 4,5,6, For 7,7 &amp; -octahydroindole-2-carboxylic acid or a pharmaceutically acceptable salt thereof, it is expected to be generated from 2,3,3 &amp;, 4,5,6,7,7 &amp;- The effect of octahydroindole-15 2-carboxylic acid or a pharmaceutically acceptable salt thereof is the ability to directly inhibit cartilage damage. In general, in a 0-day MIA mouse model, a disability tester measures the difference in posterior paw weight between the right arthritis joint and the left healthy joint of a male Wistar rat (150 g) (model 2KG ( Linton Test Equipment 20 (Linton Instrumentation, Norfolk, United Kingdom). The disability tester has a bay with an outwardly sloping front wall on the top (which can support the front foot of a mouse) And two weight-testing pads, each for the hind paw, to make this measurement easy. Then, the rats were anesthetized with isoflurane, and 1.0 mg of the ligament under the knee bone was injected into the knee joint of the right hind leg. Dan_ 72 200303748 Rose, description of the invention Iodoacetate ("ΜΙΑ"). Injecting μια into the joints will inhibit the breakdown of sugar and finally the death of surrounding chondrocytes. These mice are administered daily-step by step 2,3,3a, 4 , 5,6,7,7a · octahydroindino-2-carboxylic acid or a pharmaceutically acceptable salt or vehicle thereof (water in the example before the eyes) for 14 or 28 days. 5 2,3,3a , 4,5,6,7,7a-octahydroindole 2-carboxylic acid or a pharmaceutically acceptable salt thereof 30 kg of 2,3,3 &amp;, 4,5,6,7,7 &amp; -octahydroindole-2-carboxylic acid or its pharmaceutically acceptable salt (30 mg / kg per kg of rat per day) / Day), but may be administered in other doses depending on the needs of the compound to be studied, such as, for example, 10 g / kg / day, 60 g / kg / 10 days, 90 mg / kg / day, or 100 g G / kg / day. In this model, suitable 2'3,3 &amp;, 4,5,6,7,7 &amp; -octahydroindole-2 can be determined quite well in the level of commonly known medical skills. -Dosage of carboxylic acid or pharmaceutically acceptable salt thereof. In this model, 2,3,3 &amp;, 4,5,6,7,7 &amp; -octahydroindole-2-carboxylic acid or pharmaceutically acceptable Acceptable salts can be administered either orally or intravenously via osmotic pumps. After 7 and 14 days of the two-week study (or 7, 14, and 28 days of the four-week study) The weight distribution of the hind paw is measured again. Typically, animals administered the vehicle alone will place more weight on their left hind paw than the right hind paw; however, 2'3 , 3 &amp;, 4,5,6,7,7 &amp; -octahydroindole-2-carboxylic acid Animals with pharmaceutically acceptable salt 20 will show a more normal weight distribution between their hind paws (ie, more like a healthy animal). This change in weight distribution will be related to the degree of articular cartilage damage Proportion. The change in percent inhibition in hind paw joint function can be calculated by changing the percentage of hind paw weight distribution between treated animals and control animals. For example, for a two-week study, 73 200303748 Percent change in inhibition of joint function 1. &quot; (AWG) I · (△ Wc) • where: AWc is a control animal administered alone with a hind paw between a healthy left foot and an arthritic foot Weight difference (as measured at 14 days); and 5 AWg is 2,3,3 &amp;, 4,5,6,7,7 &amp; -octahydroindole_2-carboxylic acid or its pharmaceutically acceptable dose The difference in hind paw weight between healthy left and arthritic feet (as measured at 14 days). In order to measure the end point of biochemistry or histopathology in a mouse model of MIA, some of the animals studied above can be sacrificed, and the biopsy10 analysis was used to measure the knee joint of the right bone joint and the left knee joint on the opposite side. The amount of free proteoglycans in the subject. The amount of free proteoglycan in the contralateral left knee joint provides a baseline value for the amount of free proteoglycan in healthy joints. The amount of proteoglycan in the knee joint of the right bone joint of animals administered 2,3,3 &amp;, 4,5,6,7,7 &amp; -octaindol-2-carboxylic acid, and The amount of proteoglycan in the knee joint of the right bone joint of the 15th dose of the vehicle can be compared with the amount of proteoglycan in the left knee joint on the opposite side. The amount of proteoglycans lost in the right bone, the knee joint, is expressed as the percentage of proteoglycans lost (compared to the control left knee joint on the opposite side). The percentage of inhibition of proteoglycan loss can be {[(Proteoglycans lost from joints using a vehicle (%))-(20 using 2,3,3 ^ 4,5,6,7,7 octahydroindole- 2-Carboxylic acid and proteoglycans lost from joints)] + (Calculate protein lost from joints using a vehicle. Most MIA mouse data estimated from proteoglycan loss analysis can be established 74 200303748 发明, invention description 2, 3,3a, 4,5,6,7,7a-octahydroindole-2-carboxylic acids (including [2 (S), 3a (S), 7a (S)] _ 2,3,3a, 4,5 , 6,7,7a-octahydroindole-2 · carboxylic acid) can be effectively used to inhibit cartilage damage and treat osteoarthritis in lactating animals (including humans). Biological methods 2 5 in MIA [2 (8), 3 &amp; (8), 73 (8)]-2,3,3 &amp;, 4,5,6,7,7 &amp; -octahydro, indole_2_carboxylic acid: In a special experiment The anesthetized male Vista rats were injected with sodium iodoacetate ("MIA") (1 mg / joint) through the sub knee ligament of the right knee. The contralateral control knee was injected with 50 microliters of physiological saline. Changes in the weight distribution of the hind paws between the right (for arthritis 10) and left (for contralateral control) knees (if disability testing is available (Measured by testing machine), can be used as an indicator of knee function limitation of arthritis. Joint function limitation is measured at 7, 14, and 28 days after arthritis induction. After sacrifice, measurement is performed on tibial high mounds from arthritic joints磨 # Severity. Histological analysis was also performed in these samples. The basis of the present invention is based on [2 (8), 3 &amp; (8), 7 &amp; (8)]-2,3,3 &amp;, 4 , 5,6,7,7 &amp; -octahydroindole-2-conic acid (which is administered orally twice daily at doses of 30 mg / kg and 10 mg / kg (ie, PO; BID)) can be significantly reduced The ability of cartilage to abrasion severity, this ability to reduce joint function limitation can be contoured by reducing the difference in weight on the hind feet. 20 For oral administration, [2 (S), 3a (S), 7a (S )]-2,3,3a, 4,5,6,

7,7a-octahydro-2-carboxylic acid is dissolved in double distilled water (all calculation results are based on the percentage of the parent drug). Dose-response studies ranging from 3 to 30 mg / kg (PO; BID) can show that after 4 weeks of MIA, the doses of 30 mg / kg and 10 mg / kg are [2 (S), 3a (S), 7a (S)]-2,3,3a, 4,5,6,7,7a-A 75 200303748 玖, description of the invention Hydroindole-2-carboxylic acid can significantly reduce the degree of damage to cartilage structure, and at all doses Both can significantly reduce joint pain. The results of these oral studies are shown in the labeled column of Table 1 below: "IJFL (% + /-SEM)", where IJFL means 5 inhibition of joint function limitation; "SDCES", where SDCES means significant To reduce the severity of cartilage abrasion; and "SIJWHLE", where SIJWHLE means a significant increase in joints without the hind-foot worm I. Table 1 · Four week study, each dose of [2 (S), 3 & (8), 7 & (8)]-2,3,3 &, 4,5,6,7 , 7 & -octahydro-2-carboxylic acid: Dose (mg / kg) IJFL (% + /-SEM) a SDCESb SIJWHLE0 30 83 +/- 7 Yesd YESe 10 70 +/- 9 No YESf 3 62+ / -6 None None / No / Not 10 ⑻ρ &lt; 0.05 against vehicle (Student's t-test); (b) p &lt; 0.05 against vehicle (Ridit analysis) ; (C) ρ &lt; 0.05 paired vehicle (Exact Sequential Cochran-Armitage Trend test) i (d) actual p = 0.021; 15 (e) actual Ρ = 0.020; (f) Actual P = 0.46. [2 (S), 3a (S), 7a (S)]-2,3,3a, 4,5,6,7,7a-Octahydroindole-2-carboxylic acid compound can also be subcutaneously through osmotic pump Dosing. The administration can be performed at 100 mg / 20 kg / day, 90 mg / kg / day, 30 mg / kg / day, and 10 mg / kg / day. The results of these studies by osmotic pump administration are shown in the marked column of Table 2 below. "IJFL (% + /-SEM)", where IJFL means inhibition of joint function limitation; "SDCES", where SDCES It means Ming 76 200303748, the invention description significantly reduces the severity of cartilage erosion of the cartilage; and "SIJWHLE", where SIJWHLE means a significant increase in ± ^ ^ immediately, without back foot abrasion. Table 2. Two and four weeks of research 7a (S)]-2,3,3a, 4,5 Plant 7 ^ 'It is administered via osmotic pump [2 (S), 3a (S), ,,, 5' 7a • Octahydroindole-2-carboxylic acid: Dose during the study ) 85 +/- 3 NDd ND 4 weeks 100 78 +/- 3 No None 4 Weeks 30 94 +/- 10 No None 4 Weeks 10 28 +/- 14e No None ⑷ρ &lt; 0.05 against vehicle (Studen Special t-test); (b) p &lt; 0.05 pair vehicle (Ridt analysis); (c) ρ &lt; 0.05 pair vehicle (positive sequence Cork-Amitage trend test); ( d) ND means no measurement; {e} has no statistical significance. 10 The proportion of subjects without back foot abrasion can be analyzed by the Orthogonal Cork-Amitigi Trend Test (SAS® Association '1999). When you want To determine whether the proportion of positive or “yes,” responders will increase or decrease with the degree of treatment, use the Cork-Amitigic Trend Test. For this particular 15 separate studies, The number of animals found to have not been ablated has increased with increasing doses. Riedet analysis can be used to measure the overall The difference in the severity of erosion. This parameter simultaneously considers the degree of abrasion (0 = no abrasion, 1 = abrasion extended to the surface or intermediate layer, or 11 = deep abrasion), and the area (small, medium and large). The largest abrasion area in each scar is divided into one-half and the amount) one. This analysis can understand that the severity of each unit is different ', but a mathematical relationship cannot be assumed between units. 77 200303748 玖, invention Explain that the MIA mouse data reported in Tables 1 and 2 above can establish 2,3,3a, 4,5,6,7,7a-octahydroindole-2 · carboxylic acids (including [2 (s), 3a (s), 7a (S)] _ 2,3,3a, 4,5,6,7,7a-octahydro, hydrazone-2 · carboxylic acid) can effectively prevent or treat cartilage damage. 5 Biological methods 3 Rabbit Osteoarthritis Induction Experiment ("Rabbit's EOA"): Anesthetize normal rabbits and make an anterior mid-incision of the right knee. Make the anterior cruciate ligament fully visible and section. Close the wound and place the animals in each In cages, exercise and feed at will. These rabbits provide vehicle 10 (water) or [2 (8), 3 邶) 57 邶)] _ 2,3,3 &amp;, 4,5,6,7, 7 heart octahydroindole _2_Brancid or its pharmaceutically acceptable salts (10 rabbits per group). Each group takes the medicine daily [2 (8), 3 &amp; (8), 7 &amp; (8)]-2,3,3 &amp;, 4,5,6,7,7 &amp; -octahydroindole-2-carboxylic acid or a pharmaceutically acceptable salt thereof twice, each group received 30 mg / kg / dose or 10 mg / kg / dose . After 8 weeks, the rabbits were euthanized, and surgery was performed to remove the proximal end of the tibia and the distal end of the femur from each animal. Macroscopically classified under a dissecting microscope (Stere〇z〇〇m), Bao District &amp; Lamb (Bausch & Lomb, Rochester, Νγ), each pair in the femoral condyle The cartilage on the tibia and the tibial high mound were graded. Abrasion depth of 20 degrees is divided into grades of 0 to 4 as follows: Grade 0 = normal surface; grade 1 = minimal fibrillation or slight yellowish discoloration on the surface; grade 2 = abrasion only extends to the surface or intermediate layer · Level 3 = Abrasion is extended to deep layers; Grade Abrasion is extended to bones under the cartilage. Surface area changes are measured and expressed in square millimeters. Typical samples can also be used for histological classification (see below). 78 200303748 发明, description of the invention Histological classification Histological evaluation was performed on the sagittal section of the cartilage from the lesion area of the femoral condyles and tibial high mounds. Serial sections (5 microns) were prepared and stained with saffron-0. The severity of injury in OA can be divided into grades 0 to 5, which can be observed by two independent observers using the histology-histochemistry grade of Mankin et al. This grade assesses the severity of OA damage based on the following: loss of saffron-〇 staining (grade 0-4), cellular changes (grade 0-3), invasive invasion of blood vessels (grade (M), and structural changes (grade 〇6). On this latter level, 〇 indicates normal cartilage structure, while 6 indicates 10 that cartilage wears down to the bone below the cartilage. The scoring system uses the most stringent histological changes in most sections as A typical sample of the synovial film from the middle and lateral knee space can be dissected from the underlying tissue. The sample is fixed, embedded, and sectioned (5 microns) 'as described above and stained with hematoxylin and eosin. For each cavity, examine two 15 samples of the synovial film for scoring purposes, keeping the highest score for each cavity. Calculate this average score and consider it to be a unit for the entire knee. Synovium The severity of inflammation can be divided into grades 0 to 10 by two independent observers adding 3 histological criteria scores. Synovial-lined cell proliferation (grade 0-2), villous proliferation (grade; and by single Cell infiltration of nucleus and polymorphonuclear cells Degree (level 0 · 5) ·· 0 is a normal structure. Statistical analysis of π-ten mean and SEM, and statistical analysis using Mann-Whitney U-test. Results of these studies will be expected Can show 2,3,3a, 4,5,6,7,7a · octahydro 79 200303748 Rose, invention description. Induced 2-acid acid or its pharmaceutically acceptable salts (including [2⑻, 3a⑻, 7 &amp; (8)]-2,3,3 &amp;, 4,5,6,7,7 &amp; -octahydroindole-2-carboxylic acid), will reduce the size of the lesion on the south tibia (perhaps in the tibia) Or damage to the femoral chain process). In summary, these results will show 2,3,3 &amp;, 4,5,6,7,7 ^ octahydro-5indolecarboxylic acid or its pharmaceutically acceptable salt (Including [2 (S), 3a (S), 7 &amp; (8)]-2,3,3 &amp;, 4,5,6,7,7 &amp; -octahydroindole-2-carboxylic acid), can It has a significant inhibitory effect on cartilage damage. The aforementioned research will establish 2,3,3a, 4,5,6,7,7a &quot; \ indole-2-carboxylic acid or its pharmaceutically acceptable salts (including [2 (s), 3a (S), 7a (S)] _ 10 2,3,3 &amp;, 4,5,6,7, -octahydroindole-2-carboxylic acid), can be effectively used Inhibit human cartilage damage and cure Treatment of osteoarthritis, and other mammalian conditions. This treatment can provide a significant advantage over existing treatments that can only modify pain and other secondary symptoms. 2,3,3a, 4,5,6,7,7a · Octahydroindole-2-carboxylic acid or a pharmaceutically acceptable salt thereof (including [2 (s), 3a⑻, 7a⑻] -2,3,3μ, 5,6, 15 7,7a_octahydro ' -2-carboxylic acid) in this model will indicate that 2,3,3 &, 4,5,6,7,7 & -octahydroindole-2-carboxylic acid or its pharmaceutically acceptable Salts (including [2 (8), 3 &amp; (8), 7 &amp; (8)] _ 253,3 &amp;, 4,5,6,7,7 &amp; -octahydroindole-2-carboxylic acid) prevent and There will be useful clinical effects in treating cartilage damage. According to the method of the present invention, 2,3,3 &amp;, 4,5,6,7,7 octahydroindole-2-20 carboxylic acid or a pharmaceutically acceptable salt thereof is administered to a mammal for therapeutic scheduling In the above-mentioned diseases, this can preferably (but not necessarily) be achieved by administering the compound or a salt thereof in a pharmaceutical dosage form. 2'3,3 &amp;, 4,5,6,7,7 octahydroindole-2-carboxylic acid or a pharmaceutically acceptable salt thereof can be prepared into a wide variety of oral and 80 200303748 (ii) Description of the invention Enteral pharmaceutical dosage forms and administration. Therefore, 2,3,3a, 4,5,6,7,7a-octahydroindole-2-carboxylic acid or a pharmaceutically acceptable salt thereof can be administered by injection, that is, intravenously, intramuscularly Intradermal, intradermal, subcutaneous, intraduodenal or intraperitoneal. Similarly, 2,3,3 &amp;, 4,5,6,7,7 &amp; -octahydroindole-2-carboxylic acid or its pharmaceutically acceptable salt can be obtained by inhalation (for example, intranasal ) Dosing. Additionally, 2,3,3 &amp;, 4,5,6,7,7 &amp; -octaindol-2-carboxylic acid or a pharmaceutically acceptable salt thereof can be administered transdermally. It will be apparent to those skilled in the art that the following dosage forms may contain 2,3,3 &amp;, 4,5,6,7,7 &amp; -octahydroindole-2-carboxylic acid or an acceptable salt thereof As an active ingredient. These active compounds are typically present in the formulation at a concentration of from about 5% to about 95% by weight. For the preparation of a pharmaceutical composition from 2,3,3 &amp;, 4,5,6,7,7 &amp; -octahydroin-2-acid or a pharmaceutically acceptable salt (ie, active ingredient) thereof That said, the pharmaceutically acceptable carrier can be a solid or a liquid. Solid form preparations are preferred. The solid form preparations include powders, lozenges, pills, capsules, tablets, suppositories and dispersible granules. The solid carrier can be one or more substances which can also be used as diluents, flavoring agents, dissolving agents, lubricants, suspending agents, binders, preservatives, pastille-decomposing agents, or capsule materials. In powders, the carrier may be a finely divided solid in a mixture containing the finely divided active ingredient. Powders suitable for intravenous administration of 20 drugs or injections can be lyophilized. In the lozenge, the active ingredient and the carrier having the required cohesive properties can be mixed in a suitable ratio and compacted into the desired shape and size. These powders and lozenges preferably contain a total of about 5% to about 70% of the active ingredient. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose 81 200303748 玖, description of the invention, pectin, dextrin, starch, gelatin, Tragacons gum, methyl cellulose, and methyl cellulose Sona, low-flavored tincture, cocoa butter and its analogs. The name "formulation" is intended to include a formulation containing an active set of 'knife's encapsulating the material as a carrier, which can provide a live sex component (with or without other carriers) surrounded by a carrier (which therefore binds it) Capsule. Similarly, this includes tablets and key bonds. Bonding agents, powders, capsules, pills, tablets and lozenges can be used as solid dosage forms suitable for oral administration. To prepare suppositories, a low melting wax (such as a mixture of fatty acids, glycerols, or cocoa butter) is first melted, and if active, the knife is dispersed homogeneously by stirring. This homogeneous molten mixture is then poured into a suitably sized mold and allowed to cool, thereby solidifying. Liquid form preparations include solutions, suspensions and emulsions, such as water or water propylene glycol solutions. For parenteral injection, the liquid preparation can be formulated in a solution of an aqueous polyethylene glycol solution. 15 Aqueous solutions suitable for oral use can be prepared by dissolving the active ingredient in water and adding suitable coloring agents, seasonings, stabilizers and thickening agents, if desired. Aqueous suspensions suitable for oral use can be obtained by dispersing the finely divided active ingredient in a viscous substance such as natural or synthetic gum, resin 20, methyl cellulose, μmethyl cellulose sodium and others Phase # well-known suspending agent) in water. Also included are solid form preparations which are intended to be converted to liquid form preparations for oral administration immediately before use. This liquid form includes solutions, suspensions and emulsions. These formulations may include (in addition to the active ingredient) coloring 82 200303748, tinctures, flavoring agents, stabilizers, buffers, artificial and natural sweeteners, dispersants, gelling agents, solubility agents, and the like. The pharmaceutical preparation is preferably in a unit dosage form. In this form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form may be a packaged preparation in a vial or ampoule, the package containing individual preparations (such as encapsulated lozenges, tablets, and powders). Likewise, the unit dosage form may be a capsule, lozenge, tablet, or buccal tablet itself, or it may be any suitable number of these in a packaged form. The amount of the active ingredient in the unit dosage formulation may be changed or adjusted from 0.01 to 1000 mg, preferably 1 to 500 μg, depending on the particular application and the effectiveness of the 10 active ingredient. The composition may also contain other compatible therapeutic agents if necessary. In the use of a therapeutic agent for treating the diseases listed above, the 2,3,3 &amp;, 4,5,6,7,7 &amp; -octahydroindole-2-carboxylic acid or a pharmaceutically acceptable The received salt (or a combination thereof with vardecoxib) is a dose effective to treat at least one symptom of the disease or condition to be treated. An effective starting dose of the active ingredient per day is about 1 mg / kg to about 100 g / kg. The daily dosage range of the active ingredient is preferably from about 25 mg / kg to about 75 mg / kg. However, these doses can be based on the needs of the patient, the severity of the 20 symptoms to be treated, and 2,3,3 &amp;, 4,5,6,7,7 &amp; -octahydroindole_2-carboxylic acid or its medicine. On acceptable salts (or combinations used). The determination of a suitable dosage for a particular situation is within the well-known techniques described above. Typical dosages are from about 0.1 mg / kg to about 500 mg / kg, ideally from about 25 mg / kg to about 250 mg. / Kg, so it will be an effective amount to treat the disease or condition to be treated. For dogs, the 'preferable composition includes an orally ingestible liquid dosage form' which may be selected from the group consisting of a solution, suspension, emulsion, inverse emulsion, medicine, extract, tincture and concentrate, which Can be optionally added to drinking water for dogs who want to treat 5 treatments. Any of these liquid dosage forms (when formulated according to methods well known in the art) may be administered directly to the dog to be treated or may be added to the drinking water of the dog to be treated. On the other hand, a concentrated liquid form can be formulated by first adding a prescribed amount of water, and then removing a liquid amount that can be administered directly to the dog or added to the dog's drinking water. Preferred compositions can provide delayed, sustained, and / or controlled release 2'3'38,4,5,6,7,7 &amp; -octahydro 5 budol-2-latonic acid or its pharmaceutically acceptable Of salt. This preferred composition includes all of these dosage forms which produce 240% inhibition of cartilage deterioration and produce an active ingredient plasma concentration of at least 3 times the ED &quot; of the active ingredient for at least 2 hours; preferably at least 2 hours 4 hours; 15 is preferably at least 8 hours; more preferably at least 12 hours, still more preferably at least 16 hours; even more preferably at least 20 hours; and most preferably at least 24 hours. Preferably, those dosage forms described above include an active ingredient plasma concentration that produces 240% inhibition of cartilage deterioration and produces an EDw of at least 5 times the active ingredient for at least 2 hours, and preferably at least 2 hours. 2 hours, 20 is preferably at least 8 hours, more preferably at least 12 hours, still more preferably at least 20 hours and most preferably at least 24 hours. More preferably, the dosage form described above comprises an active ingredient plasma concentration that produces 250% inhibition of cartilage deterioration and produces an EDw of at least 5 times the active ingredient for at least 2 hours, preferably at least 4 hours, It is preferably at least 8 hours, more preferably at least 12 hours, 84 200303748, still more preferably at least 20 hours and most preferably at least 24 hours. The following examples illustrate the pharmaceutical composition of the present invention, which contains an effective amount for treating cartilage damage or an effective amount for anti-bone joints. 2,3,3a, 4,5,6,7,7a_octahydroindole-2-carboxylic acid And a pharmaceutically acceptable carrier, diluent or excipient. &quot; These examples are for illustrative purposes only and are not intended to be inferred as a limitation of the invention in any relevant respect. Formulation Example 1 Lozenge Formula: Ingredient Amount (mg) [2 (8), 3 &amp; (8), 7 &amp; (8)]-2,3,3 &amp;, 4,5,6,7々-octahydroindolin Indole-2-acid 25 lactose 50 corn flour (for mixing) 10 corn flour (paste) 10 magnesium stearate (1%) total 5 100 will be [2 (S), 3a (S), 7a (S )]-2,3,3a, 4,5,6,7,7a_ Octahydroindole-2-carboxylic acid 10, lactose and corn flour (for mixing) are mixed uniformly. Corn flour (for paste) was suspended in 200 ml of water and heated to stir to form a paste. The paste was used to make the mixed powder into granules. The wet granules were passed through a No. 8 hand sieve and dried at 80 t. The dried granules were lubricated with 1% magnesium stearate and pressed into a lozenge. This lozenge can be administered to 15 humans 1 to 4 times a day to suppress cartilage damage or treat osteoarthritis. Formulation Example 2 Coated Lozenges: Coat the Lozenges of Formulation Example 丨 with a sucrose, horse 85 200303748 玖, a description of the invention potato starch, talc, Tragacons gum and coloring agent in a conventional manner. Of coating. Formulation Example 3 Injection vial = 500 grams of [2 (8), 38 (8), 7 &amp; (8)]-2,3,3 &amp;, 4,5,6,7,73-octahydroindane The pH of the solution of 5-2-carboxylic acid and 5 g of disodium hydrogen phosphate was adjusted to ρΗ6.5 by using 2M hydrochloric acid with 3 liters of double distilled water. This solution was aseptically filtered, and the filtrate was filled into injection vials, bead-dried under aseptic conditions, and hermetically sealed. Each injection vial contains 25 mg of [2 (8), 3 &amp; (8), 7 Zhuang (8)]-2,3,3 &amp;, 4,5,6,7,7 &amp; -octahydrogen Indole-2-carboxylic acid. 10 Formulation Example 4 Suppository = 25 grams of [2 (11), 3 & (11), 7 &amp; (1〇) -2,3,3 &amp; 54,5,6,7,7 &amp; -octahydroindole A mixture of -2-carboxylic acid, 100 grams of soy lecithin, and 1400 grams of cocoa butter was melted and poured into a mold and allowed to cool. Each suppository contained 25 mg of 15 [2 (Chem.), 3 &amp; (Magic, 7 &amp; (11)]-2,3,3 &amp;, 4,5,6,7,7 &amp; -octahydro-2-acid. Formulation Example 5 Solution: The solution can be from 1 g of [ 2 (S), 3a (R), 7a (R)]-2,3,3a, 4,5,6,7,7a-octahydroindole · 2-carboxylic acid, 9.38 g of NaH2P04 · 12H20, 28.48 20 grams of 20 Na2HP〇4 · 12H2O and 0.1 grams of gasified benzalkonium ammonium were prepared in 940 ml of double-distilled water. The pH of the solution was adjusted to pH 6.8 using 2M hydrochloric acid. The solution was diluted to ι · liter and sterilized by irradiation. A 25 liter volume solution contained 25 mg of [2⑻, 3 &lt; κ), 7 &amp; (ι ^ _ 2,3,3 &amp;, 455,6,7 , 7 &amp; -Octahydroport-introduced Duo-2-chinic acid. 86 200303748 玖, Description of Invention Formula Example 6 敕 Cream: 500 mg of [2 (R), 3a (S), 7a (R)]-2 , 3,3a, 4,5,6,7,7a-octahydroindole-2-carboxyl Mixed with 99.5 grams of petroleum jelly under sterilized conditions 5. 5 grams of partial ointment contains 25 mg of [2 (11), 3 &amp; (8), 7 &amp; (11)]-2,3,3 &amp;, 4,5,6,7,7 &amp; -octahydrogen | Hou_2-acid acid. Formulation Example 7 Capsule: 2 kg [2 (S), 3a (S), 7a (S) in a conventional manner )]-2,3,3a, 4,5,6, 10 7,7a-octahydroindole-2-carboxylic acid is filled into hard gelatin capsules, so each capsule contains 25 mg of [2 (8) , 3 &amp; (8), 7 &amp; (8)]-2,3,3 &amp;, 4,5,6,7,7 &amp; -octahydro-2-acid. Formulation Example 8 Ampoule: 15 2.5 [2 (8), 3 &amp; (8), 7 &amp; (11)]-253,3 &amp;, 4,5,6,7,7 &amp; -octahydroindole-2-carboxylic acid solution dissolved in 60 Liters of double distilled water. The solution was sterile filtered, and the filtrate was filled into ampoules. The ampoules were lyophilized and sterilized and sealed. Each ampule contained 25 mg of [2 (8), 3 &amp; (8), 7 &amp; (^)-2,3,3 &amp;, 4,5,6,7,7 &amp; -octahydroindole-2-carboxylic acid. 20 The following examples illustrate the pharmaceutical composition of the present invention, which comprises a combination of the present invention and a pharmaceutically acceptable carrier, diluent or excipient. These examples are for display only, and are not intended to be inferred as limitations of the present invention in any relevant respect. 0 87 200303748 玖, Invention Description Formula Example 9 Lozenge formula: _ amount of Mog) 25 20 50 10 10 5 120 Ingredients [2 (8), 3 &amp; (3), 7 &amp; (8)]-2,3,3 &amp;, 4,5,6,7 &gt; -octahydroindole_2-carboxylic acid valdecoxib lactose corn flour (for mixing ) Cornmeal (paste) Magnesium stearate (1%) Total [2 (S), 3a (S), 7a (S)]-2,3,3a, 4,5,6,7,7a -Octahydro ηbow n _ acid, valdecoxib, lactose and corn flour (for mixing) are mixed. 5 meters of jade flour (for paste) is suspended in 200 ml of water and heated to form a paste. The paste was used to make the mixed powder into granules. The granules of the 4 tide seat were passed through a No. 8 hand net and dried at 80 °. Gully dry granules are lubricated with 1% magnesium stearate and pressed into a lozenge. This lozenge can be administered to humans 1 to 4 times a day to treat the diseases listed above. 10 Formulation Example 10 Coated Lozenges ... The lozenges of Formulation Example 9 were coated in a conventional manner with a coating of sucrose, potato starch, talc, teragacons gum, and tinting agent. Formulation Example 11 15 This shot vial contains 250 grams of valdecoxib, 500 grams of [2 (s), 3a (s), 7a (s)] _ 2'3'3 &amp; 4,5,6 , 7,7 &amp; -octahydroindole_2-carboxylic acid and 5 g of disodium hydrogen phosphate solution 88 200303748 玖, PH value of the invention, adjusted to ρΗ6 with 3M double distilled water using 2M hydrochloric acid · 5. The solution was sterilized, and the filtrate was filled into an injection vial, in a sterile state; dried, and sealed with sterilization treatment. Each injection vial contains 12.5 gram of valdecoxib and 25 5 of 5 (2⑻, 3a ⑻, 7a -2) -2,3,3M, 556,757a_ Octazone ㈣Rebel Formula Example 12 Suppository: Melted 50 A mixture of valdecoxib, 25 2,3,3a, 4,5,6,7,7a-octahydroindole · 2 · carboxylic acid, 100 g of soybean lecithin, and 10 1400 g of cocoa butter, Pour it into the mold and let it cool. Each suppository contains 50 g of vardecoxib and 25 g of [2 (11), 3 &amp; (11), 7 &amp; (11)] _ 2,3,3 &amp;, 4,5,6,7,7 &amp; -Octahydroindole-2-carboxylic acid. Formulation Example 13 Solution: 15 The solution can be from 0.5 g of vardecoxib, 1 g of [2 (S), 3a (R), 7a (S)] _ 2,3,3a, 4,5,6,7, 7a-octahydroindole-2-carboxylic acid, 9.38 grams of NaH2P04 · 12H20, 28.48 grams of Na2HP04 · 12H20, and 0.1 grams of ammonium chloride were prepared in 940 liters of double distilled water. The pH of the solution was adjusted to pH 6 · 8 using 2M hydrochloric acid. This solution was diluted by 20 to 1.0 liters with double distilled water and sterilized by irradiation. A 25-litre volume solution contains 12.5 mg of vardecoxib and 25 mg of [2 (8), 3 &amp; (11), 7 &amp; (8)]-2,3 '3a, 4,5,6,7, 7 a · Octazine π induces 2-acid acid. Formulation Example 14 Ointment: 89 200303748 玖, description of the invention: 100 mg of vardecoxib, 500 mg of [2⑻, 3a⑻, 7 &amp; (8)]-2,3,3 &amp;, 4,5,6,7,7 &amp; -Octahydro, indole-2-carboxylic acid and 99.4 grams of petrolatum are mixed under sterilized conditions. 5 g of partial ointment contains 5 g of vardecoxib and 25 mg of [2 (S), 3a (S), 7a (S)]-2,3,3a, 4,5,6,7,7a-5 Octahydro, Homo-2-rebel acid. Formulation Example 15 Capsules = 2 kg of vardecoxib and 20 kg of [2 (S), 3a (S), 7a (S)]-2,3,3a, 4,5,6,7, 7a-Octahydroindino-2-Chinic Acid is filled into 10 hard gelatin capsules, so each capsule contains 25 mg of vardecoxib and 250 mg of [2 (8), 3 冱 (8), 7 &amp; (8) ] _2,3,3 &amp;, 4,5,6,7,7 &amp; -octahydro-2-carboxylic acid. Formulation Example 16 Ampoules: 15 Put 2.5 kg of vardecoxib and 2.5 kg of [2 (S), 3a (S), 7 &amp; (8)]-2,3,3 &amp;, 4,5,6,7,7 &amp; -Octahydroindino-2-carboxylic acid solution was dissolved in 60 liters of double distilled water. The solution was sterile filtered, and the filtrate was filled into an ampoule. The ampoule is lyophilized in a sterile state and hermetically sealed. Each ampoule contains 25 mg of vardecoxib and [2 (S), 3a (S), 7a (S)] _ 20 2,3,3 a, 4,5,6,7,7a. Throat-2-rebellion. Although you want to combine valdecoxib with ^ ⑻ ^ ⑻ 心 ⑻] -2,3,3 &amp;, 4,5,6,7,7 &amp; -octahydroindole-2-carboxylic acid or a pharmaceutically acceptable salt thereof Formulated together in a capsule, lozenge, ampoule, solution, and the like for simultaneous administration, but this is not necessary for the purpose of performing the method of the present invention. Furthermore, 'Vardecoxib of the present invention and [2 (s), 3a⑻, ~ ⑻] 2,3,33,4,5,6,7,73-octahydrotendo_2_carboxylic acid or its pharmaceutically acceptable Each of the accepted salt combinations can be individually formulated into any form (such as any one of Formulae 16 to 16) and can be administered simultaneously or at different times. The following examples illustrate the pharmaceutical composition of the present invention, which comprises individual formulations of the active ingredients of the combination of the present invention and a pharmaceutically acceptable carrier, diluent or excipient. These examples are for illustrative purposes only and are not intended to be in any way related to the limitations of the present invention. Formulation example 17 MJm2 (S.)? 3a (S) Ja (S) 1-2,3,3a, 4.5.6 7 7 ,, λ

Corn flour (for mixing) Corn flour (paste) Magnesium stearate (1%) 10 10 5 100 10 Total [2 (S), 3a (S), 7a (S)]-2,3,3a , 4,5,6,7,7a · octahydro, indole-2-acid, milk bran and corn flour (used for mixing) and mix well. Corn flour (for paste) is suspended in 200 ml of water and heated to stir to form a paste. The paste was used to make the mixed powder into granules. The wet particles were passed through a No. 8 hand screen and dried at 80 ° C. The dried granules were lubricated with 1% magnesium stearate and pressed into a lozenge. Injectable vial formulation of Pandecopol: 500g of valdecoxib and 5g of disodium hydrogen-filled solution are adjusted to pH 91 200303748. The invention description is adjusted with 2M hydrochloric acid with 3 liters of double distilled water. To ρΗ6.5. This solution was sterile-filtered, and the filtrate was filled into an injection vial, lyophilized in a sterile state, and hermetically sealed. Each injection vial contains 25 mg of vardecoxib. 5 This bond containing [2⑻, 3a⑻, 7a⑻] -2,3,3, 4,5,6,7,7 &amp; -human indole · 2-round acid can be administered to humans 1 to 1 day 4 times for the treatment of the diseases listed above, &amp; the injection solution containing vardecoxib can be administered to humans 1 or 2 times a day, in which when used by injection, the tablets can be optionally taken simultaneously or simultaneously Administration to treat the diseases listed above. 10 Formulation Example 18 Dish-2-protective acid recording agent: In a conventional manner, the tablet of Formulation Example 17 is coated with a coating of sucrose, potato starch, talc, Tragacons gum, and coloring agent. . 15 capsules containing vandal pupar: Fill 2 kg of valdecoxib into hard gelatin capsules in a known manner, so that each capsule contains 25 mg of valdecoxib. The coated spinner containing [2 (S), 3a (S), 7a⑻] · 2 3,3M, 5,6,7,73_ octakidone-2-metanoic acid can be administered to humans for one day … Times, for the treatment of 20 diseases listed above; and the capsule containing vardecoxib can be administered ^ type once a day, wherein the capsules can be administered in the form of tablets at the same time or at different times when administered To treat the diseases listed above. Still further, it should be understood that the method of the present invention comprises administering a combination of the present invention to a mammal to treat the diseases or conditions listed above. 92 200303748 玖, description of the invention can be used to treat different diseases simultaneously. For example, a lamp-medicine combination of vardecoxib according to the present invention can be used as described above to treat inflammation, pain in arthritis, pain associated with menstrual cramps, and migraine, while 2,3,3M, 5'6 can be administered at the same time , 7,7μ Hydrodeca-2-carboxylic acid or its pharmaceutically acceptable salt 5 to treat OA or inhibit cartilage damage. As shown above, the method of the present invention can provide a disease that is significantly more preexisting for treating diseases such as OA (which includes cartilage damage) (where the existing / oral treatment modifies pain or first-level symptoms, but does not show disease improvement Sexual effects). 2,3,3a, 4,5,6,7,7a-octahydro. Indole_2_carboxylic acids (including 10 [2 (S), 3a (S), 7a (S)]-2,3,3a, 4,5,6,7,7a-octahydroindole-2- Carboxylic acid) has been shown to be useful in inhibiting cartilage damage and treating osteoarthritis. Although the invention has been described and clarified with reference to certain specific embodiments, those skilled in the art will understand that different adaptations, changes, modifications, substitutions, eliminations, or additions to these procedures and rules can be made. Without departing from the spirit and scope of the present invention. Therefore, it is intended that the present invention may be defined by the following patent application scopes, and such patent application scopes may be reasonably and broadly interpreted. The invention then claims the method described in the invention and its different specific embodiments. 20 [Brief description of the diagram] (None) [List of symbols for the main components of the equation] (None) 93

Claims (1)

200303748 A patent application method for inhibiting cartilage damage in lactating animals, which comprises administering to the lactating animals an effective amount of 2,3,3 ^ 4,5,6,7, ^ _ octahydroind Indole-2-carboxylic acid or a pharmaceutically acceptable salt thereof. 2. The method as claimed in item 1 of the May patent scope, wherein the 2,3,3a, 4,5,6,5 7,7a-octahydroindole-2-carboxylic acid or a pharmaceutically acceptable salt thereof A compound named [(), 3a (S), 7a (S)]-2,3,3a, 4,5,6,7,7a_Human Hydrogen @Bu Su-2-Jinic Acid or its medicine Acceptable salt. 3. A method for treating osteoarthritis in a mammal, comprising administering to the mammal a therapeutically effective amount of 2,3,3 &amp;, 4,5,6,7,7 02-carboxylic acid or a pharmaceutically acceptable salt thereof. 4. The method of claim 3 in the scope of patent application, wherein the 2,3,3〇, 5,6,7,7a-octahydroindole-2-carboxylic acid or a pharmaceutically acceptable salt thereof is named as [2 (S) 53a (S) 57a (S)]-2,3,3a5455,6,7,7a-octahydropione-2, an acidic compound or a pharmaceutically acceptable salt thereof. 15 5. A method for alleviating pain, inflammatory pain, pain in bones and joints, or pain caused by cartilage damage in a mammal, which comprises administering to the mammal a therapeutically effective amount of 2,3,3a, 4,5 , 6,7,7a_octahydro is called indole-2_arsinoic acid or a pharmaceutically acceptable salt thereof. 6. The method according to item 5 of the scope of patent application, wherein the 2,3,3a, 4,5,6 20 7,7a-octahydroindole-2-carboxylic acid or a pharmaceutically acceptable salt thereof is a name A compound of [2 (S), 3a (S), 7a (S)]-25353a, 4,5,6,757a &quot; L ^ .2-guineaic acid or a pharmaceutically acceptable salt thereof. 7. A pharmaceutical composition comprising a 2,3,3 &amp;, 4,5,6,7,7 ^ octahydro-2-carboxylic acid or a pharmaceutically acceptable salt thereof, and a medicine The carrier, diluent or excipient within the scope of the patent application, which can be accepted in 1994 200303748, wherein the pharmaceutical composition is a solid dosage form suitable for oral administration. 8. The pharmaceutical composition according to item 7 of the application, wherein the 2,3,3 &amp;, 4,5,6,7,7 &amp; -octahydroindole-2-carboxylic acid or a pharmaceutically acceptable compound thereof 5 Salt is a compound named [2 (S), 3a (S), 7a (S)]-2,3,3a, 4,5,6,7,7a-octahydroindole-2-carboxylic acid Or a pharmaceutically acceptable salt thereof. 9. Use of 2,3,3 &amp;, 4,5,6,7,7 &amp; -octahydroindole-2-carboxylic acid or a pharmaceutically acceptable salt thereof, which can be used to prepare a usefully Agents that suppress cartilage damage, treat osteoarthritis, or relieve pain. 10 10. The use according to item 9 of the scope of patent application, wherein the 2,3,3a, 4,5,6,7,7a-octahydroindole-2-carboxylic acid or a pharmaceutically acceptable salt thereof is one Compounds named [2 (8), 3 &amp; (8), 7 &amp; (8)]-2,3,3 &amp;, 4,5,6,7,7 &amp; -octahydroindole-2-carboxylic acid Or a pharmaceutically acceptable salt thereof. 200303748 Lu, (1), the designated representative of this case is: Figure _ (b), the representative symbols of the representative diagram are briefly explained: (None) :